Treatment of female sexual dysfunction with vasoactive agents, particularly vasoactive intestinal polypeptide and agonists thereof

ABSTRACT

Methods for treating female sexual dysfunction are provided. A pharmaceutical composition containing a vasoactive agent selected from vasoactive intestinal polypeptide (VIP) and VIP agonists is administered to the vagina and/or vulvar region of the individual undergoing treatment. The formulations are also useful for improving vaginal muscle tone and tissue health, enhancing vaginal lubrication, and minimizing excess collagen deposition. Pharmaceutical formulations and kits are also provided.

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application is a continuation-in-part of U.S. patentapplication Ser. No. 09/498,522, filed Feb. 4, 2000, which is adivisional of U.S. patent application Ser. No. 09/181,316, filed Oct.27, 1998, abandoned, which was a continuation-in-part of U.S. patentapplication Ser. No. 08/959,064, filed Oct. 28, 1997, which issued onMar. 2, 1999 as U.S. Pat. No. 5,877,216, and which was also acontinuation-in-part of U.S. patent application Ser. No. 08/959,057,also filed Oct. 28, 1997, now abandoned, the disclosures of which arehereby incorporated by reference.

TECHNICAL FIELD

[0002] This invention relates generally to methods and pharmaceuticalformulations for treating female sexual dysfunction, and moreparticularly relates to vaginal and/or vulvar administration of avasoactive agent, such as a prostaglandin or a vasoactive intestinalpolypeptide, in such treatment. The invention further relates toadditional methods of using the present pharmaceutical formulations,including, but not limited to, the prevention of yeast infections andthe improvement of vaginal muscle tone.

BACKGROUND

[0003] Sexual response in women is generally classified into fourstages: excitement, plateau, orgasm, and resolution. Masters andJohnson, Human Sexual Response (Boston, Mass.: Little, Brown & Co.,1966). With sexual arousal and excitement, vasocongestion and musculartension increase progressively, primarily in the genitals, and ismanifested by increased blood flow, elevated luminal oxygen tension, andvaginal surface lubrication as a result of plasma transudation thatsaturates the fluid reabsorptive capacity of the vaginal epithelium.Vasoactive intestinal polypeptide (“VIP”) release may induce thephysiological changes of sexual arousal and excitement, and may be themajor neurotransmitter effecting neurologically controlled increase ofthe vaginal blood supply upon arousal. The peptide histidine methioninehas been co-located with VIP within nerve fibers that innervate smallblood vessels, smooth muscle and epithelial cells in the vaginal tract.

[0004] VIP is a neurotransmitter known to effect small vessel dilationin the mesenteric blood supply in response to mechanical sensation offood in the gut to promote digestion. VIP is therefore found in thecholinergic, parasympathetic ganglia of the intestinal peripheralnervous system. Kandel, Schwartz and Jessel, Principles of NeuralScience, 4^(th) Ed. (McGraw-Hill 2000). VIP was initially discovered,isolated and purified from porcine intestine, and the twenty-eight (28)amino acid VIP has extensive homology to secretin and glucagon(Carlquist et al. (1982) Horm. Metab. Res. 14:28-29). VIP is known toexhibit a wide range of biological activities in the gastrointestinaltract and circulatory system. VIP has been shown to stimulate pancreaticand biliary secretion, hepatic glycogenolysis, glucagon and insulinsecretion and to activate pancreatic bicarbonate release (Kerrins t al.(1972) Proc. Soc. Exp. Biol. Med. 142:1014-1017; Domschke et al. (1977)Gastroenterology 73:78-480).

[0005] The physiologic effects of VIP extend outside the digestivesystem. For example, neurons containing VIP have been localized byimmunoassay in cells of the endocrine and exocrine systems, intestineand smooth muscle (Polak et al. (1974) Gut 15:720-724), and has beenfound to be a neuroeffector of the release of hormones includingprolactin (Frawley et al. (1981) Neuroendocrinology 33:79-83), thyroxine(Ahren et al. (1980) Nature 287:343-345), and the aforementioned insulinand glucagon (Schebalin, et al. (1977) Am. J. Physiology E. 232:197-200.VIP is present in neurons and neural junctions in the airways of animalspecies including man (Dey et al. (1980) Fed. Proc. 39:1062; Said et al.(1974) Ann. N.Y. Acad. Sciences 221:103-114). VIP has also been found tostimulate renin release from the kidney in vivo and in vitro (Porter etal. (1983) Neuroendocrinology 36:404-408), and the presence of VIP inother parts of the genito-urinary system has been shown. The widelyappreciated direct vasoactive effect of VIP is to increase blood flowinto capillary bed by dilation of the afferent blood vessel. Variousanalogs of VIP, both agonistic and antagonistic are known to exist (seefor example U.S. Pat. Nos. 5,235,907, 5,141,924, 4,734,400 and 4,605,641to Bolin; and U.S. Pat. Nos. 4,939,224 and 4,835,252 to Musso et al.).

[0006] Sexual excitement is initiated by any of a number of psychogenicor somatogenic stimuli and must be reinforced to result in orgasm. Withcontinued stimulation, excitement progresses in intensity into a plateaustage, from which the individual can shift into orgasm. The orgasmicstage is characterized by a rapid release from vasocongestion andmuscular tension.

[0007] During the various stages of sexual response, characteristicgenital and extragenital responses occur. Estrogens magnify the sexualresponses; however, sexual responses may also occur inestrogen-deficient individuals. Sexual dysfunction may be due to organicor functional disturbances. For example, a variety of diseases affectingneurologic function, including diabetes mellitus and multiple sclerosis,may interrupt sexual arousal. More commonly, local pelvic disorders,such as endometriosis and vaginitis, both of which cause dyspareunia(difficult or painful coitus) may also affect a woman's sexual response.In addition, estrogen deficiency, causing vaginal atrophy anddyspareunia, is a common cause of sexual dysfunction. For a discussionof other causes of female sexual dysfunction, see, e.g., Kaplan, TheEvaluation of Sexual Disorders: Psychological and Medical Aspects (NewYork, N.Y.: Brunner-Mazel, 1983), and Kolodny et al., Textbook of SexualMedicine (Boston, Mass.: Little, Brown & Co., 1979).

[0008] Excitement stage dysfunction generally involves touch sensationimpairment, loss of clitoral sensation, vaginal dryness and urinaryincontinence. Such excitement phase dysfunction generally results indyspareunia. Dyspareunia is thought to affect approximately 40% ofwomen, due in large part to inadequate lubrication. It has beenestimated that over 40 million women will suffer dyspareunia at sometime in their lives. On the order of twenty-five million women willexperience dyspareunia in the peri- and postmenopausal period (seeKelly, S. (1992) Clinical Practice and Sexuality 8(8):2 and Sato et al.(1992) Clinical Practices in Sexuality 8(5):1). Contemporary symptomatictreatments generally involve the use of physiologically safe lubricantssuch as egg white, K-Y surgical lubrication jelly(hydroxyethyl-cellulose), Astroglide7, and Replens7. See, for example,Semmens (1974) Medical Aspects of Human Sexuality 8:85-86, and Frishmenet al. (1992) Fertility and Sterility 8(3):630. When symptomatictreatment fails, pharmacological treatment may be indicated.

[0009] Estrogen therapy is commonly used in the pharmacologicaltreatment of sexual dysfunction in women. Estrogen-based therapies aregenerally used to increase mucous production, provide vasodilatoryeffects, or to increase the general health of the vagina. Nadelson etal., eds., Treatment Interventions in Human Sexuality (New York: PlenumPress, 1983). In such treatments, estrogen is administered orally,parenterally (e.g., by injection), or topically. With oraladministration, the estrogen concentration encountered by the liver isgenerally four- to five-fold greater than estrogen levels in peripheralblood (the “first pass effect”). This effect may lead to an undesirableincrease in the production of certain coagulation factors and reninsubstrates by the liver. Parenterally administered estrogen avoids thefirst pass effect in the liver. However, all estrogen-based therapiesare known to increase the risk of endometrial hyperplasia, endometrialcancer and breast cancer in treated individuals.

[0010] Because of the increased risk of endometrial hyperplasia andendometrial cancer encountered with unopposed estrogen therapies,estrogen/progestogen combinations have been employed. However,progestogens are known to have some androgenic activity. Further, commonside effects from such therapies include uterine bleeding and thecontinuation of menstrual periods. Accordingly, there remains a need inthe art to provide safer and more ways of treating female sexualdysfunction.

[0011] The present invention is directed to the aforementioned need inthe art, and provides a new, highly effective method of treating sexualdysfunction in women. The method involves vaginal and/or vulvaradministration of a pharmaceutical formulation containing a vasoactiveagent, e.g., a prostaglandin, VIP or a VIP agonist or the like.

[0012] Drug therapy for treating female sexual dysfunction has beendescribed. For example, U.S. Pat. No. 4,507,323 to Stern describes theuse of the anxiolytic m-chloro-α-t-butylamino-propiophenone in thetreatment of sexual dysfunction in both male and female individuals.Pharmaceutical compositions containing the agent are described, whichare presented in discrete units, e.g., cachets, tablets, capsules,ampules and suppositories, for oral or rectal delivery of the agent.

[0013] Additionally, U.S. Pat. No. 4,521,421 to Foreman describes thetreatment of sexual dysfunction in male and female individuals using thestereoisomers of octahydropyrimido[4,5-g]quinolines, centrally actingdopamine agonists.

[0014] U.S. Pat. No. 5,190,967 to Riley describes the treatment ofsexual disorders in male and female individuals using heterocyclicbenzodioxinopyrrole compounds, which, like the drugs described in theaforementioned patents, are centrally acting agents.

[0015] U.S. Pat. Nos. 5,565,466 to Gioco et al., 5,731,339 to Lowrey,and 5,773,457 to Nahoum pertain to methods for modulating the humansexual response, with the Gioco et al. and Lowrey patents emphasizingthe utility of phentolarnine as an active agent.

[0016] A number of references describe various methods and devicessuitable for vaginal or uterine drug administration, and may accordinglybe of some interest with respect to the present invention. The followingare representative of such references:

[0017] U.S. Pat. No. 3,967,618 to Zaffaroni describes an intrauterinedevice adapted for drug delivery. A number of drugs are mentioned asbeing suitable for use in conjunction with the device. However, thepatent does not mention treatment of sexual dysfunction, nor isapplication of a drug-containing composition to the clitoris or vulvarregion disclosed or suggested. U.S. Pat. No. 3,948,254 to Zaffaroni is arelated patent that describes an intrauterine device for continuousadministration of a contraceptive agent.

[0018] U.S. Pat. No. 4,014,987 to Heller et al. describes a tampon-likedevice for delivery of a drug to the uterus or vagina. Heller et al.mention that delivery of prostaglandins is a preferred use of theinvention; however, there is no disclosure concerning treatment ofsexual dysfunction or delivery to the vulvar area or urethra.

[0019] U.S. Pat. No. 4,564,362 to Burnhill describes a vaginal spongefor controlled release of a contraceptive agent.

[0020] U.S. Pat. No. 4,112,942 to Scaife generally describes vaginaladministration of medicinal foams.

[0021] There are, accordingly, a number of background referencesrelating to treatment of female sexual dysfunction, and cervical oruterine administration of vasoactive agents. However, the present methodfor treating female sexual dysfunction, by way of vaginal and/or vulvardelivery of a vasoactive agent such as a prostaglandin or VIP or areceptor agonist thereof, is completely novel and unsuggested by theart.

SUMMARY OF THE INVENTION

[0022] Accordingly, it is a primary object of the invention to provide amethod for treating sexual dysfunction in a female individual byadministering a pharmaceutical formulation containing a selectedvasoactive agent to the vaginal and/or vulvar area of the individualundergoing treatment.

[0023] It is still another object of the invention to provide methodsfor improving vaginal muscle tone and tissue health, enhancing vaginallubrication, preventing vaginal atrophy, preventing pain duringintercourse as a result of dyspareunia, alleviating vaginal itching anddryness associated with dyspareunia and other conditions, and minimizingcollagen misdeposition resulting from hypoxia, each of such methodsvaginal and/or vulvar administration of a pharmaceutical formulationcontaining a selected vasoactive agent, in combination with apharmaceutically acceptable vehicle.

[0024] It is an additional object of the invention to provide suchmethods wherein the vasoactive agent is vasoactive intestinalpolypeptide or an agonist thereof.

[0025] It is still an additional object of the invention to provide suchmethods wherein drug administration is carried out on an as-neededbasis.

[0026] It is a further object of the invention to provide pharmaceuticalformulations useful in conjunction with the aforementioned methods.

[0027] Additional objects, advantages and novel features of theinvention will be set forth in part in the description that follows, andin part will become apparent to those skilled in the art uponexamination of the following, or may be learned by practice of theinvention.

[0028] In one aspect of the invention, then, a method is provided fortreating sexual dysfunction in a female individual comprisingadministering to the vagina and/or vulvar area a pharmaceuticalformulation containing a selected vasoactive agent. The vasoactive agentis preferably a vasodilator, with preferred vasodilators selected fromthe group consisting of VIP and vasoactive intestinal polypeptideagonists, both natural and synthetic, and combinations of any of theforegoing. Any number of drug delivery platforms may be used, e.g.,suppositories, ointments, creams, gels, solutions and the like, whichwill be described in detail below. Also, one or more additional types ofdrugs, i.e., pharmacologically active agents other than vasoactiveagents, may be incorporated into the pharmaceutical formulations. Inother aspects of the invention, vaginal administration of a vasoactiveagent as just described is used to improve vaginal muscle tone andtissue health, to enhance vaginal lubrication, or to minimize collagenmisdeposition resulting from hypoxia as well as the associated lack ofelasticity resulting from the collagen misdeposition.

[0029] In another aspect of the invention, pharmaceutical compositionsand dosage forms are provided for carrying out the aforementionedmethods. The compositions and dosage forms contain a vasoactive agent asdescribed above, a pharmaceutically acceptable vehicle, and, optionally,one or more additional pharmacologically active agents. The formulationscontain a therapeutically effective amount of the active agent, or atherapeutically effective concentration of the active agent, i.e., aconcentration that provides a therapeutically effective amount of activeagent upon administration of a selected volume of composition.

[0030] In another embodiment, packaged kits are provided for individualsto carry out the aforementioned methods. Packaged kits include apharmaceutical composition or dosage form containing the active agent, acontainer housing the composition or dosage form during storage andprior to administration, and instructions, e.g., written instructions ona package insert or label, for carrying out drug administration in atherapeutically effective manner. The composition or dosage form may beany of those described herein.

DETAILED DESCRIPTION OF THE INVENTION

[0031] Before describing the present invention in detail, it is to beunderstood that this invention is not limited to delivery of specificdrugs, carriers or use of particular drug delivery systems, as such mayvary. It is also to be understood that the terminology used herein isfor the purpose of describing particular embodiments only, and is notintended to be limiting.

[0032] It must be noted that, as used in this specification and theappended claims, the singular forms “a,” “an” and “the” include pluralreferents unless the context clearly dictates otherwise. Thus, forexample, reference to “a vasoactive agent” includes a mixture of two ormore vasoactive agents, reference to “a pharmaceutically acceptableexcipient” includes mixtures of such excipients, and the like.

[0033] In describing and claiming the present invention, the followingterminology will be used in accordance with the definitions set outbelow.

[0034] The terms “active agent,” “pharmacologically active agent” and“drug” are used interchangeably herein to refer to a chemical compoundthat induces a desired pharmacological, physiological effect, i.e., inthis case, enhancement of female sexual desire and responsiveness. Theprimary active agents herein are vasoactive intestinal polypeptide andagonists thereof. The terms also encompass pharmaceutically acceptable,pharmacologically active derivatives of those active agents specificallymentioned herein, including, but not limited to, salts, esters, amides,prodrugs, active metabolites, and the like. When the terms “activeagent,” “pharmacologically active agent” and “drug” are used, then, itis to be understood that applicants intend to include the active agentper se as well as pharmaceutically acceptable, pharmacologically activesalts, esters, amides, prodrugs, metabolites, analogs, etc.

[0035] The pharmacologically active agents herein are vasoactiveintestinal polypeptide and analogs thereof that serve as VIP agonists.

[0036] By “pharmaceutically acceptable,” such as in the recitation of a“pharmaceutically acceptable carrier,” or a “pharmaceutically acceptableacid addition salt,” is meant a material that is not biologically orotherwise undesirable, i.e., the material may be incorporated into apharmaceutical composition administered to a patient without causing anyundesirable biological effects or interacting in a deleterious mannerwith any of the other components of the composition in which it iscontained. “Pharmacologically active” (or simply “active”) as in a“pharmacologically active” derivative or metabolite, refers to aderivative or metabolite having the same type of pharmacologicalactivity as the parent compound and approximately equivalent in degree.When the term “pharmaceutically acceptable” is used to refer to aderivative (e.g., a salt) of an active agent, it is to be understoodthat the compound is pharmacologically active as well, i.e.,therapeutically effective to enhance female sexual desire andresponsiveness.

[0037] “Carriers” or “vehicles” as used herein refer to conventionalpharmaceutically acceptable carrier materials suitable for drugadministration, and include any such materials known in the art that arenontoxic and do not interact with other components of a pharmaceuticalcomposition or drug delivery system in a deleterious manner.

[0038] By an “effective” amount or a “therapeutically effective amount”of a drug or pharmacologically active agent is meant a nontoxic butsufficient amount of the drug or agent to provide the desired effect,i.e., treatment of female sexual dysfunction. The amount that is“effective” will vary from subject to subject, depending on the age andgeneral condition of the individual, the particular active agent oragents, and the like. Thus, it is not always possible to specify anexact “effective amount.” However, an appropriate “effective” amount inany individual case may be determined by one of ordinary skill in theart using routine experimentation.

[0039] The terms “treating” and “treatment” as used herein refer toreduction in severity and/or frequency of symptoms, elimination ofsymptoms and/or underlying cause, prevention of the occurrence ofsymptoms and/or their underlying cause, and improvement or remediationof damage. Thus, for example, “treating” sexual dysfunction, as the termis used herein, encompasses both prevention of sexual dysfunction inclinically asymptomatic individuals and treatment of dysfunction in aclinically symptomatic individual.

[0040] By “treating female sexual dysfunction” is meant enhancing femalesexual desire and responsiveness. Applicants intend to include thetreatment of disorders of female sexual desire and/or response, meaningany disorder or dysfunction that causes a decrease in or absence offemale sexual responsiveness or female sexual desire. This includes anypersistent or recurrent deficiency in the desire for sexual activity. Italso includes decreases in the physiological response to sexualstimulation such as slowed or decreased erectile response of the femaleerectile tissues; slowed, decreased or absent lubrication of the vagina;slowed, decreased, or absent ability to have orgasms; decreasedintensity of or pleasure in orgasms: frigidity; sexual aversion; anddisorders of female sexual desire and response that are secondary to ageneral medical condition such as the menopausal or post-menopausalstate, radiotherapy of the pelvis, atherosclerosis, pelvic trauma orsurgery, peripheral neuropathies, autonomic neuropathies, diabetesmellitus, and disorders of the innervation of any of the sexual organs.This term also includes substance-induced sexual dysfunction, includingbut not limited to, decreases in desire and responsiveness secondary toanti-depressants, neuroleptics, anti-hypertensives, tobacco, opiates,alcohol and any other drug found to decrease or eliminate any part ofthe sexual response cycle. Primary and secondary anorgasmia areincluded.

[0041] By “as-needed” dosing, also referred to as “pro re nata” dosing,“pm” dosing, and “on-demand” dosing or administration, is meant theadministration of an active agent at a time just prior to the time atwhich drug efficacy is wanted, e.g., just prior to anticipated sexualactivity, and within a time interval sufficient to provide for thedesired therapeutic effect, i.e., enhancement in sexual desire and insexual responsiveness during sexual activity. “As-needed” administrationherein does not involve priming doses or chronic administration,“chronic” meaning administration at regular time intervals on an ongoingbasis. As-needed administration may involve administration immediatelyprior to sexual activity, but will generally be about 0.25 to 72 hours,preferably about 0.5 to 48 hours, more preferably about 1 to 24 hours,most preferably about 1 to 12 hours, and optimally about 1 to 4 hoursprior to anticipated sexual activity. “As-needed” administration may ormay not involve administration of a sustained release formulation inadvance of anticipated sexual activity, with drug release taking placethroughout an extended drug delivery period typically in the range ofabout 4 to 72 hours.

[0042] The term “controlled release” is intended to refer to anydrug-containing formulation in which release of the drug is notimmediate, i.e., with a “controlled release” formulation, oraladministration does not result in immediate release of the drug into anabsorption pool. The term is used interchangeably with “nonimmediaterelease” as defined in Remington: The Science and Practice of Pharmacy,Nineteenth Ed. (Easton, Pa.: Mack Publishing Company, 1995). Asdiscussed therein, immediate and nonimmediate release can be definedkinetically by reference to the following equation:

[0043] The “absorption pool” represents a solution of the drugadministered at a particular absorption site, and k_(r), k_(a) and k_(e)are first-order rate constants for (1) release of the drug from theformulation, (2) absorption, and (3) elimination, respectively. Forimmediate release dosage forms, the rate constant for drug release k_(r)is far greater than the absorption rate constant k_(a). For controlledrelease formulations, the opposite is true, i.e., k_(r)<<k_(a), suchthat the rate of release of drug from the dosage form is therate-limiting step in the delivery of the drug to the target area. Theterm “controlled release” as used herein includes any nonimmediaterelease formulation, including but not limited to sustained release,delayed release and pulsatile release formulations.

[0044] The term “sustained release” is used in its conventional sense torefer to a drug formulation that provides for gradual release of a drugover an extended period of time, and that preferably, although notnecessarily, results in substantially constant blood levels of a drugover an extended time period. A sustained release formulation may beadministered once to provide a single bolus dose of the active agent,which is then effective for up to a day or even up to several days.

[0045] By the term “transdermal” drug delivery is meant delivery bypassage of a drug through the skin or mucosal tissue and into thebloodstream.

[0046] The term “topical administration” is used in its conventionalsense to mean delivery of a topical drug or pharmacologically activeagent to the skin or mucosa. Topical administration thus includestransmucosal administration.

[0047] Generally, “vaginal delivery” of a pharmaceutical formulationinvolves administration to the distal several centimeters of the vagina.The terms “vulvar delivery” and “vulvar administration” are used hereinto refer to application of a pharmaceutical formulation to the vulvararea of an individual undergoing treatment. The term is intended toencompass application to the clitoris as well as the surrounding vulvararea. The terms “vulvar delivery” and “clitoral delivery” are usedinterchangeably herein and are both intended to refer to administrationto the vulvar area of the individual undergoing treatment.

[0048] In order to carry out the method of the invention, VIP or anagonist thereof is administered to the vagina and/or vulvar region of afemale individual to enhance sexual desire and responsiveness; theindividual may or may not be suffering from a sexual disorder ordysfunction. The active agent is administered locally andtransmucosally, i.e., vaginally and/or to the vulvar region.

[0049] As used herein, the term “C₁₋₃ alkyl” refers to methyl, ethyl,propyl, and isopropyl.

[0050] The nomenclature used to define the vasoactive intestinalpeptides of the invention is that typically used in the art, wherein theamino group at the N-terminus appears to the left and the carboxyl groupat the C-terminus appears to the right. By natural amino acids is meantone of the naturally occurring amino acids found in proteins, i.e., Gly,Ala, Val, Leu, Ile, Ser, Thr, Lys, Arg, Asp, Asn, Glu, Gln, Cys, Met,Phe, Tyr, Pro, Trp, and His. By Nle is meant norleucine. By Orn is meantornithine. By Ac is meant acetyl (CH₃CO₂). Where the amino acid hasisomeric forms, it is the L form of the amino acid that is representedunless otherwise expressly indicated.

[0051] Analogs of VIP, i.e., those analogs included herein as VIPagonists, are indicated by setting forth the substituted amino acid inbrackets before “VIP.” Derivatization of the N-terminal amino group isindicated to the left of the bracketed substitutions. Sequence numbersappearing in parentheses to the right of “VIP” indicate amino aciddeletions and additions to the native sequence numbering. That is, forexample, Ac-[Lys¹²,Nle¹⁷,Gly²⁹]-VIP(2-29) indicates a polypeptide havingan amino acid sequence corresponding to native human VIP in which anacetyl group has been substituted for hydrogen at the N-terminus, lysinehas been substituted for arginine at position 12 and norleucine has beensubstituted for methionine at position 17, the histidine at position 1has been deleted and a glycine has been coupled onto the carboxyl sideof asparagine 28, termed position 29. The suffixes “—OH” and “—NH₂”following “VIP” refer to the free acid and amide forms of thepolypeptide, respectively. In the event neither suffix is used, theexpression is intended to encompass both forms.

[0052] The following abbreviations are also defined: N—CH₃-Ala isN-methyl-alanine, p-F-Phe is fluoro-phenylalanine, 1-Nal is3-(1′-naphthyl)-alanine, 2-Nal is 3-(2′-naphthyl)-alanine, p-NH₂-Phe isp-amino-phenylalanine, O—CH₃-Tyr is O-methyl-tyrosine, Cys(Acm) isS-acetoamidomethyl-cysteine, m-F-Tyr is m-fluoro-tyrosine.

[0053] In a first embodiment, the invention relates to a method fortreating sexual dysfunction in a female individual and involves vaginaland/or vulvar administration of a pharmaceutical formulation containinga vasoactive agent, preferably a vasodilator. Preferred vasodilators areselected from the group consisting of vasoactive intestinal polypeptide,VIP agonists, pharmaceutically acceptable salts, esters, derivatives,prodrugs, and inclusion complexes thereof, and combinations of any ofthe foregoing, in combination with a pharmaceutically acceptablevehicle.

[0054] VIP agonists are, as noted above, useful for practicing theinvention. The sequence of human VIP, which is the same as rat, bovineand porcine VIP is known to be:

[0055]His-Ser-Asp-Ala-Val-Phe-Thr-Asp-Asn-Tyr-Thr-Arg-Leu-Arg-Lys-Gln-Met-Ala-Val-Lys-Lys-Tyr-Leu-Asn-Ser-Ile-Leu-Asn.

[0056] In the conventional single letter amino acid code the VIP aminoacid sequence is:H-S-D-A-V-F-T-D-N-Y-T-R-L-R-K-Q-M-A-V-K-K-Y-L-N-S-I-L-N (SEQ. ID. NO.:1). VIP sequences from other species are known to exhibit homology tohuman VIP and therefore expected to exhibit VIP agonistic and/orantagonistic activity. Partial agonists of VIP that are also antagonistsof VIP, for example agonists that are less active than endogenouslysecreted VIP may be used in the methods of the invention depending uponactivity relative to physiologic human VIP and local dosage. Theusefulness of partial VIP agonists for practicing the invention may beascertained by conventional trials and pharmacologic assays known in theart.

[0057] Representative vasoactive intestinal polypeptide analogs includepeptides having the following amino acid sequences:

[0058] [Lys¹², Nle¹⁷]-VIP (SEQ. ID. NO.: 2);

[0059] Ac-[Lys¹², Nle¹⁷]-VIP (SEQ. ID. NO.: 3);

[0060] [Orn¹², Nle¹⁷]-VIP (SEQ. ID. NO.: 4);

[0061] Ac-[Orn¹², Nle¹⁷]-VIP (SEQ. ID. NO.: 5);

[0062] [Ser¹¹,Phe¹³,Nle¹⁷]-VIP (SEQ. ID. NO.: 6);

[0063] Ac-[Ser¹¹,Phe¹³,Nle¹⁷]-VIP (SEQ. ID. NO.: 7);

[0064] [Nle¹⁷,Thr²⁵]-VIP (SEQ. ID. NO.: 8);

[0065] [Nle¹⁷,Thr²⁴]-VIP (SEQ. ID. NO.: 9);

[0066] [Ala⁹,Nle¹⁷]-VIP (SEQ. ID. NO.: 10);

[0067] Ac-[Ala⁹,Nle¹⁷]-VIP (SEQ. ID. NO.: 11);

[0068] [Lys¹⁴,Nle¹⁷]-VIP (SEQ. ID. NO.: 12);

[0069] [Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 13);

[0070] [Lys¹²,Lys¹⁴,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 14);

[0071] [Nle¹⁷,Thr²⁸]-VIP (SEQ. ID. NO.: 15);

[0072] Ac-[Nle¹⁷,Thr²⁸]-VIP (SEQ. ID. NO.: 16);

[0073] [Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 17);

[0074] Ac-[Orn¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 18);

[0075] Ac-[Lys¹²,Lys¹⁴,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 19);

[0076] Ac-[Lys¹²,Nle¹⁷,Thr²⁵,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 20);

[0077] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Ala²⁸]-VIP;

[0078] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Ala²⁷,Thr²⁸]-VIP (SEQ. ID. NO.: 21);

[0079] Ac-[Lys¹²,Nle¹⁷,Ala²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 22);

[0080] Ac-[Lys¹²,Nle¹⁷,Ala²⁵,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 23);

[0081] Ac-[Lys¹²,Nle¹⁷,Ala²⁴,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 24);

[0082] Ac-[Lys¹²,Nle¹⁷,Ala²³,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 25);

[0083] Ac-[Lys¹²,Nle¹⁷,Ala²²,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 26);

[0084] Ac-[Lys¹²,Nle¹⁷,Ala²¹,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 27);

[0085] Ac-[Lys¹²,Nle¹⁷,Ala²⁰,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 28);

[0086] Ac-[Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 29);

[0087] Ac-[Lys¹²,Ala¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 30);

[0088] Ac-[Lys¹²,Ala¹⁶,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 31);

[0089] Ac-[Lys¹²,Ala¹⁵,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 32);

[0090] Ac-[Lys¹²,Ala¹⁴,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 33);

[0091] Ac-[Lys¹²,Ala¹³,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 34);

[0092] Ac-[Ala¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 35);

[0093] Ac-[Ala¹¹,Lys¹²,Nle¹⁷,Val²⁶Thr²⁸]-VIP (SEQ. ID. NO.: 36);

[0094] Ac-[Ala¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 37);

[0095] Ac-[Ala⁹,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 38);

[0096] Ac-[Ala⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 39);

[0097] Ac-[Ala⁷,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 40);

[0098] Ac-[Ala⁶,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 41);

[0099] Ac-[Ala⁵,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 42);

[0100] Ac-[Ala³,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 43);

[0101] Ac-[Ala²,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 44);

[0102] Ac-[Ala¹,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 45);

[0103] Ac-[Gly¹,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 46);

[0104] Ac-[Leu⁵,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 47);

[0105] Ac-[1-Nal⁶,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 48);

[0106] Ac-[p-F-Phe⁶,Lys¹²,Nle¹⁷,Val 26,Thr²⁸]-VIP (SEQ. ID. NO.: 49);

[0107] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 50);

[0108] Ac-[2 -Nal¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 51);

[0109] Ac-[p-NH₂-Phe¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 52);

[0110] Ac-[O—CH₃-Tyr¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 53);

[0111] Ac-[Lys¹² Nle¹⁷,m-F-Tyr²²,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 54);

[0112] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Met³¹]-VIP (SEQ. ID. NO.:55)

[0113] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP (SEQ. ID.NO.: 56);

[0114] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Thr³¹]-VIP (SEQ. ID. NO.:57);

[0115] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Ala^(29,30),Met³¹]-VIP (SEQ. ID. NO.:58);

[0116] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Ala²⁹⁻³¹]-VIP (SEQ. ID. NO.: 59);

[0117] Ac-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly²⁹,Lys³⁰]-VIP (SEQ. ID. NO.: 60);

[0118] Ac-[Lys¹², 14,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 61);

[0119] Ac-[2-Nal¹⁰,Lys¹²,Ala¹⁷,Val_(26,)Thr²⁸]-VIP (SEQ. ID. NO.:62);

[0120] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Ala^(29,30),Met³¹]-VIP (SEQ. ID.NO.: 63);

[0121] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Phe³¹]-VIP (SEQ. ID. NO.:64);

[0122]Ac-[p-F-Phe⁶,Glu⁸,Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 65);

[0123] Ac-[p-F-Phe⁶,p-NH₂-Phe¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID.NO.: 66);

[0124] Ac-[Lys¹²,Ala¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP (SEQ. ID.NO.: 67);

[0125] Ac-[Glu⁸,Lys^(12,14),Nle¹⁷,Val²⁶, Thr²⁸,Gly^(29,30),Met³¹]-VIP(SEQ. ID. NO.: 68);

[0126] Ac-[p-NH₂-Phe¹⁰,Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.:69);

[0127]Ac-[p-F-Phe⁶,Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 70);

[0128] Ac-[Glu⁸,Lys¹² Ala^(17,19),Val²⁶,Thr²⁸,Gly^(29,30),Met³¹]-VIP(SEQ. ID. NO.: 71);

[0129] Ac-[Glu⁸Lys¹²,Nle^(17,)Val²⁶ Thr²⁸,Gly^(29,30),Ala³¹]-VIP (SEQ.ID. NO.: 72);

[0130] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸,Gly^(29,30),Met³¹]-VIP(SEQ. ID. NO.: 73);

[0131]Ac-[p-F-Phe⁶,Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 74);

[0132] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Ser³¹]-VIP (SEQ. ID.NO.: 75);

[0133] Ac-[p-F-Phe⁶,Glu⁸,Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸]-VIP (SEQ. ID.NO.: 76);

[0134] Ac-[Glu⁸,Orn¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 77);

[0135] Ac-[Lys¹²Nle¹⁷,Ala²⁵,Leu²⁶Lys^(27,28),Gly^(29,30),Thr³¹]-VIP(SEQ. ID. NO.: 78);

[0136] Ac-[Glu⁸,Lys¹²,Nle⁷,Val²⁶,Thr²⁸,Ala²⁹⁻³¹]-VIP (SEQ. ID. NO.: 79);

[0137] Ac [Lys¹²,Ala^(17,19),Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 80);

[0138] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly²⁹,Lys³⁰]-VIP (SEQ. ID. NO.:81);

[0139]Ac-[p-HN₂-Phe¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 82);

[0140] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Cys (Acm)³¹]-VIP(SEQ. ID. NO.: 83);

[0141] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Met³¹]-VIP (SEQ. ID.NO.: 84);

[0142] CH₃S(CH₂)₂CO-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP(2-28) (SEQ. ID. NO.:85);

[0143] CH₃SO(CH₂)₂CO-[Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP(2-28) (SEQ. ID. NO.:86);

[0144] Ac-[N—CH₃-Ala₁,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 87);

[0145]Ac-[Leu⁵,Orn¹²,Ala^(17,19),Thr²⁵,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 88);

[0146] Ac-[p-F-Phe⁶,2-Nal¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Met³¹]-VIP (SEQ. ID. NO.:89);

[0147]Ac-[p-F-Phe⁶,Glu⁸,Lys^(12,14),Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 90).

[0148] Particularly common vasoactive intestinal polypeptide analogsknown in the art include the following:

[0149]Ac-[p-F-Phe⁶,Lys¹²,Nle¹⁷Ala¹⁹,Val²⁶,Thr²⁸Gly^(29,30)Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 91);

[0150] Ac-[Leu⁵,Orn¹²,Ala¹⁷Thr²⁵,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP (SEQ. ID. NO.: 92);

[0151]Ac-[p-F-Phe⁶,Glu⁸,Lys¹²,Nle¹⁷,Ala¹⁹,Val²⁶,Thr²⁸,Gly^(29,30),Cys(Acm)³¹]-VIP(SEQ. ID. NO.: 93);

[0152] Ac-[N-Me-Ala¹,Lys¹²Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 94);

[0153] Ac-[p-F-Phe⁶,p-NH₂-Phe¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID.NO.: 95);

[0154] Ac-[Glu⁸ Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Met³¹]-VIP (SEQ. ID.NO.: 96);

[0155] Ac-[p-NH₂-Phe¹⁰,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 97);

[0156] Ac-[Glu⁸,Lys¹²,Nle¹⁷,Val²⁶,Thr²⁸,Gly^(29,30),Cys (Acm)³¹]-VIP(SEQ. ID. NO.: 98).

[0157] Other VIP analogs known in the art include:

[0158] [Nle.sup.¹⁷]-VIP (SEQ. ID. NO.: 99);

[0159] Ac-[Nle.sup.¹⁷]-VIP (SEQ. ID. NO.: 100);

[0160] [Tyr⁶]-VIP (SEQ. ID. NO.: 101);

[0161] [Phe²²]-VIP (SEQ. ID. NO.: 102);

[0162] [Ser⁷]-VIP (SEQ. ID. NO.: 103);

[0163] [Lys⁷]-VIP (SEQ. ID. NO.: 104);

[0164] [Gln⁷]-VIP (SEQ. ID. NO.: 105);

[0165] [Asn⁷]-VIP (SEQ. ID. NO.: 106);

[0166] [Arg⁷]-VIP (SEQ. ID. NO.: 107);

[0167] [Arg⁹]-VIP (SEQ. ID. NO.: 108);

[0168] [Gln⁹]-VIP (SEQ. ID. NO.: 109);

[0169] [Lys⁹]-VIP (SEQ. ID. NO.: 110);

[0170] [Leu⁹]-VIP (SEQ. ID. NO.: 111);

[0171] [Ser⁹] (SEQ. ID. NO.: 112);

[0172] [Thr⁹]-VIP (SEQ. ID. NO.: 113);

[0173] [Leu¹¹]-VIP (SEQ. ID. NO.: 114);

[0174] [Lys¹¹]-VIP (SEQ. ID. NO.: 115);

[0175] [Asn¹¹]-VIP (SEQ. ID. NO.: 116);

[0176] [Gln¹¹]-VIP (SEQ. ID. NO.: 117);

[0177] [Arg¹¹]-VIP (SEQ. ID. NO.: 118);

[0178] [Thr¹⁶]-VIP (SEQ. ID. NO.: 119);

[0179] [Ser¹⁶]-VIP (SEQ. ID. NO.: 120);

[0180] [Leu¹⁶]-VIP (SEQ. ID. NO.: 121);

[0181] [Lys¹⁶]-VIP (SEQ. ID. NO.: 122);

[0182] [Asn¹⁶]-VIP (SEQ. ID. NO.: 123);

[0183] [Arg¹⁶]-VIP (SEQ. ID. NO.: 1243);

[0184] [Arg²⁴]-VIP (SEQ. ID. NO.: 125);

[0185] [Gln²⁴]-VIP (SEQ. ID. NO.: 126);

[0186] [Lys²⁴]-VIP (SEQ. ID. NO.: 127);

[0187] [Leu²⁴]-VIP (SEQ. ID. NO.: 128);

[0188] [Ser²⁴]-VIP (SEQ. ID. NO.: 129);

[0189] [Ser¹²]-VIP (SEQ. ID. NO.: 130);

[0190] [Ser²⁰]-VIP (SEQ. ID. NO.: 131);

[0191] [Orn²⁰]-VIP (SEQ. ID. NO.: 132);

[0192] [Arg²⁰]-VIP (SEQ. ID. NO.: 133);

[0193] [Phe²³]-VIP (SEQ. ID. NO.: 134);

[0194] [Phe²⁶]-VIP (SEQ. ID. NO.: 135);

[0195] [Tyr¹³]-VIP (SEQ. ID. NO.: 136);

[0196] [Tyr²³]-VIP (SEQ. ID. NO.: 137);

[0197] [Tyr²⁶]-VIP (SEQ. ID. NO.: 138);

[0198] [Leu²⁶]-VIP](SEQ. ID. NO.: 139);

[0199] [Ile¹³]-VIP (SEQ. ID. NO.: 140);

[0200] [Ile²³]-VIP (SEQ. ID. NO.: 141);

[0201] [Val¹³]-VIP (SEQ. ID. NO.: 142);

[0202] [Val²³]-VIP (SEQ. ID. NO.: 143);

[0203] [Nle¹³]-VIP (SEQ. ID. NO.: 144);

[0204] [Nle²³]-VIP (SEQ. ID. NO.: 145);

[0205] [Nle²⁶]-VIP (SEQ. ID. NO.: 146);

[0206] [Arg²¹]-VIP (SEQ. ID. NO.: 147);

[0207] [Leu¹⁴]-VIP (SEQ. ID. NO.: 148);

[0208] [Leu²¹]-VIP (SEQ. ID. NO.: 149);

[0209] [Orn¹⁴]-VIP (SEQ. ID. NO.: 150);

[0210] [Orn²¹]-VIP (SEQ. ID. NO.: 151);

[0211] [Nle¹⁴]-VIP (SEQ. ID. NO.: 152);

[0212] [Nle²¹]-VIP (SEQ. ID. NO.: 153);

[0213] [Arg¹⁵]-VIP (SEQ. ID. NO.: 154);

[0214] [Ser¹⁵]-VIP (SEQ. ID. NO.: 155);

[0215] [Gln¹⁵]-VIP (SEQ. ID. NO.: 156);

[0216] [Orn¹⁵]-VIP (SEQ. ID. NO.: 157);

[0217] [Met¹⁹]-VIP (SEQ. ID. NO.: 158);

[0218] [Leu¹⁷]-VIP (SEQ. ID. NO.: 159);

[0219] [Leu¹⁹]-VIP (SEQ. ID. NO.: 160);

[0220] [Val¹⁷]-VIP (SEQ. ID. NO.: 161);

[0221] [Lys¹⁷]-VIP (SEQ. ID. NO.: 162);

[0222] [Lys¹⁹]-VIP (SEQ. ID. NO.: 163);

[0223] [Ile¹⁷]-VIP (SEQ. ID. NO.: 164);

[0224] [Ile¹⁹]-VIP (SEQ. ID. NO.: 165);

[0225] [Nle¹⁹]-VIP (SEQ. ID. NO.: 166);

[0226] [Leu¹⁸]-VIP (SEQ. ID. NO.: 167);

[0227] [Asn²⁵]-VIP (SEQ. ID. NO.: 168);

[0228] [Leu²⁵]-VIP (SEQ. ID. NO.: 169);

[0229] [Gln²⁵]-VIP (SEQ. ID. NO.: 170);

[0230] [Val²⁷]-VIP (SEQ. ID. NO.: 171);

[0231] [Phe³]-VIP (SEQ. ID. NO.: 172);

[0232] [Tyr³]-VIP (SEQ. ID. NO.: 173);

[0233] [Phe⁷]-VIP (SEQ. ID. NO.: 174);

[0234] [Tyr⁷]-VIP (SEQ. ID. NO.: 175);

[0235] [Phe¹⁹]-VIP (SEQ. ID. NO.: 176);

[0236] [Tyr¹⁹]-VIP (SEQ. ID. NO.: 177);

[0237] [Thr⁴]-VIP (SEQ. ID. NO.: 178);

[0238] [Ser⁴]-VIP (SEQ. ID. NO.: 179);

[0239] [Asn⁴]-VIP (SEQ. ID. NO.: 180);

[0240] [Gln⁴]-VIP (SEQ. ID. NO.: 181);

[0241] [Thr⁶]-VIP (SEQ. ID. NO.: 182);

[0242] [Ser⁶]-VIP (SEQ. ID. NO.: 183);

[0243] [Asn⁶]-VIP (SEQ. ID. NO.: 184);

[0244] [Gln⁶]-VIP (SEQ. ID. NO.: 185);

[0245] [Ala⁶]-VIP (SEQ. ID. NO.: 186);

[0246] [Thr⁸]-VIP (SEQ. ID. NO.: 187);

[0247] [Ser⁸]-VIP (SEQ. ID. NO.: 188);

[0248] [Asn⁸]-VIP (SEQ. ID. NO.: 189);

[0249] [Gln⁸]-VIP (SEQ. ID. NO.: 190);

[0250] [Ser²⁸]-VIP (SEQ. ID. NO.: 191);

[0251] [Gln²⁸]-VIP (SEQ. ID. NO.: 192);

[0252] [Gln¹²]-VIP (SEQ. ID. NO.: 193);

[0253] [Gln²⁰]-VIP (SEQ. ID. NO.: 194);

[0254] [Ser²¹]-VIP (SEQ. ID. NO.: 195);

[0255] [Gln²¹]-VIP (SEQ. ID. NO.: 196);

[0256] [Met¹³]-VIP (SEQ. ID. NO.: 197);

[0257] [Ile¹⁷]-VIP (SEQ. ID. NO.: 198);

[0258] [Met²³]-VIP (SEQ. ID. NO.: 199);

[0259] [Met²⁶]-VIP (SEQ. ID. NO.: 200).

[0260] The preceding list of VIP agonists is by way of example ratherthan limitation, and other known VIP agonists include permutations ofthe preceding amino acid sequences and lesser-included deviations fromthe VIP sequence. Permutations include, for example sequences such as[Thr¹⁸]-VIP (SEQ. ID. NO.: 201), which is not listed explicitly abovebut is a lesser-included deviation from the naturally occurring humanVIP sequence that is described, for example, inAc-[Lys¹²,Nle¹⁷,Val²⁶,Ala²⁷,Thr²⁸]-VIP (SEQ. ID. NO.: 21) andAc-[Lys¹²,Nle¹⁷,Ala¹⁶,Thr²⁸]-VIP (SEQ. ID. NO.: 22), as well as a numberof other of the above listed VIP analog sequences, for example, SEQ. ID.NO.: 46. Further a permutation of SEQ. ID. NO. 21 and SEQ. ID. NO. 22,is exemplified by Ac-[Lys¹²,Nle¹⁷,Ala²⁶,Ala²⁷,Thr²⁸]-VIP (SEQ. ID. NO.:202), which substitutes the Ala²⁶ of SEQ. ID. NO.:22 for the Val²⁶ ofSEQ. ID. NO.: 21 and is otherwise identical to SEQ. ID. NO.:21.

[0261] Analogs for use with the instant invention are intended that areessentially equivalent to an explicitly disclosed analog, as specifiedabove. An analog is essentially equivalent to one specified above if ithas one or more of the biological activities characteristic of humanVIP, has the same number of amino acids as the specified analog and, incomparison with the sequence of the specified analog, has at most fiveamino acid substitutions, all of which would be considered neutral inthe art (i.e., acidic for acidic, basic for basic, uncharged polar foruncharged polar, hydrophobic for hydrophobic, and the like). As iswidely known: acidic amino acids are Asp, Glu and gamma-carboxyglutamicacid; basic amino acids are Arg, Lys, His and Orn; hydrophobic aminoacids are Ala, Ile, Leu, Met, Nor, Phe, Trp, Tyr, Val, t-butylglycine,norvaline, cyclohexylalanine, t-butylalanine, amino-4-phenylbutyricacid, beta-2-thienylalanine, p-bromophenylalanine,p-chlorophenylalanine, p-iodophenylalanine, p-nitrophenylalanine,3,5-diiodotyrosine, phenylglycine, and naphthylalanine; uncharged polaramino acids are Asn, Gln, Ser, and Thr. Gly can be substituted for anuncharged polar or a hydrophobic amino acid, but substitutions with Glyare often avoided because helical structures may be destabilizedthereby. Substitutions with Pro are generally avoided because of asignificant effect on secondary structure of inserting a Pro in place ofanother amino acid. Substitutions with Cys are also generally avoidedbecause of the reactivity of the sulfhydryl group.

[0262] Various synthetic VIP analogs, including many of the above, areexplicitly listed in U.S. Pat. Nos. 5,235,907, 5,141,924, 4,734,400 and4,605,641 to Bolin, and in U.S. Pat. Nos. 4,939,224 and 4,835,252 toMusso et al.

[0263] Other suitable VIP agonists include conjugates of VIP and longchain fatty acids or fatty amines, such as CH₃(CH₂)₆CO-VIP,CH₃(CH₂)₁₆CO-VIP, CH₃(CH₂)₁₆CO-VIP₇₋₂₈, CH₃(CH₂)₁₆CO-VIP₁₆₋₂₈,VIP-CONH—CH₂CH₃, VIP-CONH—(CH₂)₃CH₃, and VIP-CONH-(CH₂)₇CH₃, thesynthesis of which is described in U.S. Pat. No. 5,147,855 to Gozes etal.

[0264] Still other suitable VIP agonists are nitrosylated VIP analogshaving the structure VIP-Gly-Cys-NO (SEQ. ID NO.: 203), and the relatedanalogs VIP-Gly-Cys-NH₂ (SEQ. ID NO.: 204) and VIP-Gly-Cys (SEQ. ID NO.:205), preparation of which is described in U.S. Pat. No. 5,612,314 toStamler et al.

[0265] VIP analogs known in the art that are useful for practicing thepresent invention include those compounds listed above and others thatexhibit agonistic VIP activity, preferably strong agonistic activity.Also preferred are those analogs that exhibit agonistic activity with arelatively long biological activity, e.g. a relatively longpharmacologic half-life. Methods for determining the agonistic VIPactivity and half-life of a given VIP analog are known to thoseordinarily skilled in the art. One attribute of a VIP analog that makesit useful for practicing the invention is a resistance to hydrolysis, aproperty of synthetic VIP analogs that are disclosed in U.S. Pat. No.4,939,224 to Musso et al. for bronchodilation.

[0266] As the practice of the instant invention will often if nottypically involve topical delivery of the vasoactive VIP agonists to thefemale sex organs, absorption of the VIP analog through the epitheliumcovering the organ or organs to which it is applied is required for thedesired pharmacologic effects. The ordinarily skilled artisan in thetherapeutic pharmaceutical art will be able to ascertain whether theabsorption of a particular VIP analog is sufficient for the desiredeffects. VIP analogs are expected to be capable of crossing suchepithelial barriers, as the peptide is small relative to proteins.

[0267] The ability of VIP peptides to cross such epithelial barriers hasbeen demonstrated in the context of administering VIP by inhalation forbronchodilation. Although administration by inhalation has been shown tobe more tissue specific and to have fewer side-effects than intravenousadministration but appears to be less effective than intravenousadministration (Altiere et al. (1983) Pharmacologist 25:123; Bundgaardet al. (1983) Eur. J. Respir. Dis. 64(Suppl. 128):427-429; Altiere etal. (1984) Chest 86:153-154. This observed lower efficacy of VIP inbronchodilation when administered by inhalation, compared withadministration intravenously, is thought to be caused by one or acombination of: (1) rapid degradation of VIP by compounds, includingproteolytic enzymes, present in the respiratory tract both in thebronchial airways and the passageways leading thereto (Barrowcliffe etal. (1986) Thorax 41:88-93); or (2) limited absorption of VIP throughnasal and pulmonary mucosa, due in part to the size of VIP (about 3300Daltons)(Effros and Mason (1982) Am. Rev. Resp. Dis. 127:S59-S65;Altiere et al. (1984) supra).

[0268] In the context of the present invention, the ability of variousVIP analogs that exhibit VIP agonist activity to cross the pertinentepithelial barrier as a naked peptide is expected. Further, those ofskill in the art will appreciate that the ability of VIP agonists tocross the epithelial barrier of the female genitalia for use with theinstant invention may be enhanced by known techniques, such as packagingin liposomes or the like.

[0269] The above representative VIP analogs may be readily synthesizedby known conventional techniques for forming a peptide linkage betweenamino acids. Such conventional procedures include, for example, allsolution phase techniques permitting a condensation between the freealpha amino group of an amino acid or residue thereof having itscarboxyl group or other reactive groups protected and the free primarycarboxyl group of another amino acid or residue thereof having its aminogroup or other reactive groups protected.

[0270] The process for synthesizing the representative compounds may becarried out by a procedure whereby each amino acid in the desiredsequence is added one at a time in succession to another amino acid orresidue thereof or by a procedure whereby peptide fragments with thedesired amino acid sequence are first synthesized conventionally andthen condensed to provide the desired peptide.

[0271] Such conventional procedures for synthesizing the active agentsof the present invention include for example any solid phase peptidesynthesis method. In such a method the synthesis of the active agentscan be carried out by sequentially incorporating the desired amino acidresidues one at a time into the growing peptide chain according to thegeneral principles of solid phase methods (Merrifield (1963) J. Amer.Chem. Soc. 85:2149-2154; Barany et al, The Peptides, Analysis, Synthesisand Biology, Vol. 2, 1-284 Gross, E. and Meienhofer, J., Eds. (AcademicPress 1980)).

[0272] The chemical syntheses of peptides is widely appreciated torequire the protection of reactive side chain groups of the variousamino acid moieties, in addition to α-amino or α-carboxyl group of thereacted amino acids, with suitable protecting groups which will preventa chemical reaction from occurring at that site until the protectinggroup is ultimately removed. Groups requiring such protection include:α-amino, side chain-amino, carboxyl, hydroxyl, side chain amide,guanidino and imidazole. Methods for protecting both reactive side chaingroups and α-amino or α-carboxyl groups are known in the art andenumerated in U.S. Pat. Nos. 5,235,907, 5,141,924, 4,734,400 and4,605,641 to Bolin. Although the synthetic organic methods described inthe preceding publications may be employed to synthesize VIP analogsdescribed above, many may also be expressed in eukaryotic or prokaryoticcells by use of the appropriate expression vector.

[0273] Additional pharmacologically active agents may be co-administeredalong with the primary active agent, i.e., with the VIP or VIP agonist.Such additional active agents are also referred to herein as “secondary”active agents. Preferred secondary agents are vasoactive agents,particularly vasodilators, selected from the group consisting ofvasoactive prostaglandins, endothelin-derived relaxation factors, smoothmuscle relaxants, leukotriene inhibitors, pharmaceutically acceptablesalts, esters, analogs, derivatives, prodrugs, active metabolites, andinclusion complexes thereof, and combinations of any of the foregoing.Other suitable secondary agents include rho kinase inhibitors,melanocortin peptides, endothelin antagonists, growth factors and otherpeptidyl drugs; selective androgen receptor modulators (SARMs),neuropeptides, amino acids, serotonin agonists, serotonin antagonists,calcium channel blockers, potassium channel openers, potassium channelblockers, dopamine agonists, dopamine antagonists, non-androgenicsteroid hormones, and combinations thereof.

[0274] Particularly preferred vasoactive agents are vasoactiveprostaglandins selected from the group consisting of naturally occurringprostaglandins, semisynthetic prostaglandins, synthetic prostaglandins,and pharmaceutically acceptable, pharmacologically active salts, esters,amides, inclusion complexes prodrugs, metabolites, and analogs thereof.Racemic, optically enriched or purified stereoisomers of any of thesecompounds are also included. A suitable unit dose of a prostaglandinherein is in the range of approximately 1 to 5000 μg, preferably in therange of approximately 20 to 2000 μg. Preferred prostaglandins include,but are not limited to, the naturally occurring prostaglandinsprostaglandin E₀ (PGE₀, also referred to 13,14-dihydro-PGE₁,hereinafter, the abbreviation “PG” is used for “prostaglandin”), PGE₁,19-hydroxy-PGE₁, PGE₂, 19-hydroxy-PGE₂,PGA₁, 19-hydroxy-PGA₁, PGA₂,19-hydroxy-PGA₂, PGB₁, 19-hydroxy-PGB₁, PGB₂, 19-hydroxy-PGB₂, PGB₃,PGD₂, PGF_(1α), PGF_(2α),(dinoprost), PGE₃, PGF_(3α), PGI₂(prostacyclin), and combinations thereof. PGE₀, PGE₁, PGE₂, and thehydrolyzable lower alkyl esters thereof (e.g., the methyl, ethyl andisopropyl esters) are, however, particularly preferred. Other suitableprostaglandins are exemplified, without limitation, by arboprostil,carbaprostacyclin, carboprost tromethamine, dinoprost tromethamine,dinoprostone, enprostil, iloprost, lipoprost, gemeprost, metenoprost,sulprostone, tiaprost, viprostil (CL 115,347), viprostil methyl ester,16,16-dimethyl-Δ²-PGE₁, methyl ester,15-deoxy-16-hydroxy-16-methyl-PGE₁, methyl ester (misoprostol),16,16-dimethyl-PGE₁, 11-deoxy-15-methyl-PGE₁,16-methyl-18,18,19,19-tetrahydrocarbacyclin,16(RS)-15-deoxy-16-hydroxy-16-methyl-PGE₁, methyl ester,(+)-4,5-didehydro-16-phenoxy-α-tetranor-PGE₂ methyl ester, 11-deoxy-11α,16,16-trimethyl-PGE₂, (+)-11α, 16α,16β-dihydroxy-1,9-dioxo-1-(hydroxymethyl)-16-methyl-trans-prostene,9-chloro-16,16-dimethyl-PGE₂, 16,16-dimethyl-PGE₂, 15(S)-15-methyl-PGE₂,9-deoxy-9-methylene-16,16-dimethyl-PGE₂, potassium salt,19(R)-hydroxy-PGE₂, and 11-deoxy-16,16-dimethyl-PGE₂.

[0275] Additional vasoactive agents useful as secondary active agentsherein include endothelin-derived relaxation factors (“EDRFs”) such asnitric oxide releasing agents, e.g., sodium nitroprusside and diazeniumdiolates, or “NONOates.” NONOates include, but are not limited to,(Z)-1-{N-methyl-N-[6-(N-methyl-ammoniohexyl)amino]}diazen-1-ium-1,2-diolate(“MAHMA/NO”),(Z)-1-[N-(3-ammoniopropyl)-N-(n-propyl)amino]-diazen-1-ium-1,2-diolate(“PAPA/NO”), (Z)-1-{N-[3-aminopropyl]-N-[4-(3-aminopropylammonio)butyl]amino}diazen-1-ium-1,2-diolate(spermine NONOate or “SPER/NO”) and sodium(Z)-1-(N,N-diethylamino)-diazen-1-ium-1,2-diolate (diethylamine NONOateor “DEA/NO”) and derivatives thereof). Still other vasoactive agentsinclude vasoactive intestinal polypeptide analogs and derivativesthereof (particularly derivatives in the form of hydrolyzable loweralkyl esters), smooth muscle relaxants, leukotriene inhibitors, calciumchannel blockers, β2-adrenergic agonists, angiotensin-converting enzyme(“ACE”) inhibitors, angiotensin II receptor antagonists, andphosphodiesterase inhibitors.

[0276] Still other suitable vasoactive agents include, but are notlimited to: nitrates and like compounds such as nitroglycerin,isosorbide dinitrate, erythrityl tetranitrate, amyl nitrate,molsidomine, linsidomine chlorhydrate (“SIN-1”),S-nitroso-N-acetyl-d,1-penicillamine (“SNAP”) andS-nitroso-N-glutathione (“SNO-GLU”); long and short acting α-blockerssuch as phenoxybenzamine, dibenamine, doxazosin, terazosin,phentolamine, tolazoline, prazosin, trimazosin, alfuzosin, tamsulosinand indoramin; ergot alkaloids such as ergotamine and ergotamineanalogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline,delorgotrile, disulergine, ergonovine maleate, ergotamine tartrate,etisulergine, lergotrile, lysergide, mesulergine, metergoline,metergotamine, nicergoline, pergolide, propisergide, proterguride andterguride; antihypertensive agents such as diazoxide, hydralazine andminoxidil; nimodepine; pinacidil; cyclandelate; dipyridamole;isoxsuprine; chlorpromazine; haloperidol; yohimbine; and trazodone.

[0277] Other secondary active agents herein are inhibitors of rhokinase, an enzyme belonging to the rhoA/rho associated kinase pathway,which regulates the state of phosphorylation of myosin phosphatase, inturn leading to the control of smooth muscle contraction. One example ofa suitable rho kinase inhibitor has the structural formula

[0278] and is identified as Y-27632. Other suitable rho kinaseinhibitors are disclosed, for example, in U.S. Pat. No. 6,218,410.

[0279] Additional secondary agents useful herein are peptide analogs ofα-melanocyte-stimulating hormone (α-MSH), also referred to as“melanocortin peptides.” Such peptides include the sequenceHis-Phe-Arg-Trp, His-D-Phe-Arg-Trp, or are homologs thereof, and arepreferably cyclic. A preferred melanocortin peptide isAc-Nle-cyclo-(-Asp-His-D-Phe-Arg-Trp-Lys)—OH. See U.S. Pat. No.6,051,555 to Hadley and International Patent Publication No. WO 01/00224to Blood et al., assigned to Palatin Technologies, Inc. Theaforementioned amino acid residues have their conventional meaning asgiven in Chapter 2422 of the Manual of Patent Examining Procedure(2000). Thus, “Arg” is arginine, “Nle” is norleucine, “His” ishistamine, “Phe” is phenylalanine, “D-Phe” is D-phenylalanine, “Trp” istryptophan, and “Ac” refers to an acetyl moiety, i.e., an acetyl moietypresent in a peptide or amino acid sequence that is acetylated.

[0280] Suitable endothelin antagonists include antagonists of any or allof the three isoforms of endothelin, i.e., ET-1, ET-2, and ET-3, and areexemplified by: phenoxyphenylacetic acids and derivatives thereof, suchasN-(4-isopropylbenzene-sulbonyl)-α-(4-carboxy-2-n-propylphenoxy)-3,4-methylenedioxyphenylacetamide dipotassium salt,2-[(2,6-dipropyl-4-hydroxymethyl)-phenoxy]-2-(4-phenoxyphenyl)-aceticacid, 2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(4-phenylphenyl)aceticacid,2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3-carboxyphenyl)-aceticacid,2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4-ethylenedioxyphenyl)aceticacid,2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4,5-trimethoxyphenyl)aceticacid,2-[(2,6-dipropyl-4-hydroxymethyl)phenoxy]-2-(3,4-methylenedioxyphenyl)aceticacid,N-(4-dimethylaminobenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide,N-(2-methylbenzenesulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide,N-(2-methoxycarbonyl-benzenesulfonyl)-2-(4-methoxy-carbonyl-2-propylphenoxy)-2-(3,4-methylenedioxy-phenyl)acetamide,N-(2-chlorobenzene-sulfonyl)-2-(4-methoxycarbonyl-2-propylphenoxy)-2-(3,4-methylenedioxyphenyl)acetamide,and others, as described in U.S. Pat. No. 5,565,485; and certainisooxazoles, oxazoles, thiazoles, isothiazoles and imidazoles, asdescribed, for example, in U.S. Pat. No. 6,136,828. Numerous otherendothelin antagonists may be used as secondary agents herein, and willbe known to those of ordinary skill in the art and/or are described inthe pertinent patents, literature and texts.

[0281] Peptidyl drugs include the peptidyl hormones activin, amylin,angiotensin, atrial natriuretic peptide (ANP), calcitonin, calcitoningene-related peptide, calcitonin N-terminal flanking peptide, ciliaryneurotrophic factor (CNTF), corticotropin (adrenocorticotropin hormone,ACTH), corticotropin-releasing factor (CRF or CRH), epidermal growthfactor (EGF), follicle-stimulating hormone (FSH), gastrin, gastrininhibitory peptide (GIP), gastrin-releasing peptide,gonadotropin-releasing factor (GnRF or GNRH), growth hormone releasingfactor (GRF, GRH), human chorionic gonadotropin (hCH), inhibin A,inhibin B, insulin, luteinizing hormone (LH), luteinizinghormone-releasing hormone (LHRH), α-melanocyte-stimulating hormone,β-melanocyte-stimulating hormone, γ-melanocyte-stimulating hormone,melatonin, motilin, oxytocin (pitocin), pancreatic polypeptide,parathyroid hormone (PTH), placental lactogen, prolactin (PRL),prolactin-release inhibiting factor (PIF), prolactin-releasing factor(PRF), secretin, somatotropin (growth hormone, GH), somatostatin (SIF,growth hormone-release inhibiting factor, GIF), thyrotropin(thyroid-stimulating hormone, TSH), thyrotropin-releasing factor (TRH orTRF), thyroxine, and vasopressin. Other peptidyl drugs are thecytokines, e.g., colony stimulating factor 4, heparin bindingneurotrophic factor (HBNF), interferon-α, interferon α-2a, interferonα-2b, interferon α-n3, interferon-β, etc., interleukin-1, interleukin-2,interleukin-3, interleukin-4, interleukin-5, interleukin-6, etc., tumornecrosis factor, tumor necrosis factor-α, granuloycte colony-stimulatingfactor (G-CSF), granulocyte-macrophage colony-stimulating factor(GM-CSF), macrophage colony-stimulating factor, midkine (MD), andthymopoietin.

[0282] Selective androgen receptor modulators (SARMs) include LGD2226and/or LGD1331, both available from Ligand Pharmaceuticals (San Diego,Calif.). See Negro-Villar et al. (1999) J. Clin. Endocrinol. & Metabol.84(10):3459-62.

[0283] Suitable neuropeptides include bradykinin, kallidin, des-Arg⁹-bradykinin, des-Arg¹⁰-kallidin, des-Arg⁹-[Leu⁸]-bradykinin,[D-Phe⁷]-bradykinin, HOE 140, neuropeptide Y, calcitonin gene-relatedpeptide (cGRP), enkaphalins and related opioid peptides such asMet⁵-enkaphalin, Leu⁵-enkephalin, α-, β- and γ-endorphin, α- and β-neo-endorphin, and dynorphin, as well as the neurotransmitters GABA(γ-aminobutyric acid), glycine, glutamate, acetylcholine, dopamine,epinephrine, 5-hydroxytryptamine, substance P, serotonin, andcatecholamines.

[0284] One or more amino acids may be included in the presentformulations. As used herein, the term “amino acid” includes theconventional amino acids, e.g., phenylalanine, leucine, isoleucine,methionine, valine, serine, proline, threonine, alanine, tyrosine,histidine, glutamine, asparagine, lysine, aspartic acid, glutamic acid,cysteine, tryptophan, arginine, and glycine, with arginine beingparticularly preferred. In addition, the term “amino acid” will alsoinclude amino acid derivatives, e.g., 1-naphthylalanine,2-naphthylalanine, 3-pyridylalanine, 4-hydroxyproline, O-phosphoserine,N-acetylserine, N-formylmethionine, 3-methylhistidine, 5-hydroxylysine,and nor-leucine, in addition to stereoisomers (e.g., D-amino acids) ofthe twenty conventional amino acids. Combinations of any of theforegoing are contemplated as well. Preferred amino acids are theneuroactive amino acids γ-aminobutyric acid (GABA), glycine, β-alanine,taurine, and glutamate.

[0285] Suitable serotonin agonists include, but are not limited to2-methyl serotonin, buspirone, ipsaperone, tiaspirone, gepirone, ergotalkaloids, 8-hydroxy-(2-N,N-dipropyl-amino)-tetraline,1-(4-bromo-2,5-dimethoxyphenyl)-2-aminopropane, cisapride, sumatriptan,m-chlorophenylpiperazine, trazodone, zacopride, mezacopride, andcombinations thereof. Suitable serotonin antagonists include, forexample, ondansetron, granisetron, metoclopramide, tropisetron,dolasetron, palonosetron, trimethobenzamide, methysergide, risperidone,ketanserin, ritanserin, clozapine, amitriptyline, MDL 100,907(R(+)-α-(2,3-dimethoxyphenyl)-1-[2-(4-fluorophenyl)ethyl]-4-piperidine-methanol)(Marion Merrell Dow), azatadine, cyproheptadine, fenclonine,chlorpromazine, mianserin and combinations thereof.

[0286] Representative ergot alkaloids include ergotamine and ergotamineanalogs, e.g., acetergamine, brazergoline, bromerguride, cianergoline,delorgotrile, dihydroergotamine, disulergine, ergonovine, ergonovinemaleate, ergotamine tartrate, etisulergine, lergotrile, lysergide,mesulergine, metergoline, metergotamine, nicergoline, pergolide,propisergide, proterguride and terguride.

[0287] Calcium channel blockers that are suitable for use according tothe present invention include, without limitation, amlodipine,felodipine, isradipine, nicardipine, nifedipine, nimodipine,nisoldipine, nitrendipine, bepridil, diltiazem, verapamil, andcombinations thereof.

[0288] Potassium channel openers include, but are not limited to,pinacidil, diazoxide, cromakalim, nicorandil, minoxidil,(N-cyano-N′-(1,1-dimethylpropyl)-N″-3-pyridyl-guanidine (P-1075), andN-cyano-N′-(2-nitroxyethyl)-3-pridinecarboximidamidemonomethanesulfonate (KRN 2391).

[0289] Potassium channel blockers include tedisamil, agitoxin-2, apamin,BDS-I, BDS-II, charybdotoxin, α-dendrotoxin, β-dendrotoxin,γ-dendrotoxin, δ-dendrotoxin, dendrotoxin-I, dendrotoxin-K, E-4031,iberiotoxin, kaliotoxin, MCD-peptide, margatoxin, noxiustoxin,paxilline, penitrem A, stichodactyla, tertiapin, tityustoxin K alpha,verruculogen, and combinations thereof. Although all of the activeagents are available commercially, most of the listed potassium channelblockers are available from Alomone Labs (Jerusalem, Israel).

[0290] Suitable dopamine agonists include, for example, levodopa,bromocriptine, pergolide, apomorphine, piribedil, pramipexole,ropinirole, and combinations thereof. Dopamine antagonists include,without limitation, spiroperidol, benperidol, trifluperidol, pimozide,fluphenazine, droperidol, haloperidol, thiothixene, trifluperazine,moperone, prochlorperazine, molindone, thioridazine, clozapine,chlorpromazine, promazine, sulpiride, clebopride, chlorpromazine,spiperone, flupenthixol, and combinations thereof.

[0291] Non-androgenic steroids that may be administered as secondaryactive agents include progestins and estrogens. Suitable estrogensinclude synthetic and natural estrogens such as: estradiol (i.e.,1,3,5-estratriene-3,17β-diol, or “17β-estradiol”) and its esters,including estradiol benzoate, valerate, cypionate, heptanoate,decanoate, acetate and diacetate; 17α-estradiol; ethinylestradiol (i.e.,17α-ethinylestradiol) and esters and ethers thereof, includingethinylestradiol 3-acetate and ethinylestradiol 3-benzoate; estriol andestriol succinate; polyestrol phosphate; estrone and its esters andderivatives, including estrone acetate, estrone sulfate, and piperazineestrone sulfate; quinestrol; mestranol; and conjugated equine estrogens.Suitable progestins include acetoxypregnenolone, allylestrenol,anagestone acetate, chlormadinone acetate, cyproterone, cyproteroneacetate, desogestrel, dihydrogesterone, dimethisterone, ethisterone(17α-ethinyltestosterone), ethynodiol diacetate, flurogestone acetate,gestadene, hydroxyprogesterone, hydroxyprogesterone acetate,hydroxyprogesterone caproate, hydroxymethylprogesterone,hydroxymethylprogesterone acetate, 3-ketodesogestrel, levonorgestrel,lynestrenol, medrogestone, medroxyprogesterone acetate, megestrol,megestrol acetate, melengestrol acetate, norethindrone, norethindroneacetate, norethisterone, norethisterone acetate, norethynodrel,norgestimate, norgestrel, norgestrienone, normethisterone, andprogesterone. It is generally desirable to co-administer a progestinalong with an estrogen so that the estrogen is not “unopposed.” As iswell known in the art, estrogen-based therapies are known to increasethe risk of endometrial hyperplasia and cancer, as well as the risk ofbreast cancer, in treated individuals. Co-administration of estrogenicagents with a progestin has been found to decrease the aforementionedrisks.

[0292] The primary vasoactive agent—i.e., VIP or an agonist thereof—andthe additional active agent or agents may be incorporated into a singleformulation, or they may be administered separately, eithersimultaneously or sequentially. In a preferred embodiment, an androgenicagent is administered prior to administration of VIP or a VIP agonist,i.e., the androgenic agent is administered as a pretreatment. In aparticularly preferred embodiment, such a method involves administrationof an androgenic agent, e.g., via oral or topical (preferably vulvarand/or vaginal) administration, followed by topical (again, preferablyvulvar and/or vaginal) administration of VIP or a VIP agonist.

[0293] The formulations herein are administered by topical applicationto the vulvar region and/or by vaginal drug administration. Thesepharmaceutical formulations will typically contain one or morepharmaceutically acceptable carriers suited to the particular type offormulation, i.e., gel, ointment, suppository, or the like. The vehiclesare comprised of materials of naturally occurring or synthetic originthat do not adversely affect the active agent or other components of theformulation. Suitable carriers for use herein include water, silicone,waxes, petroleum jelly, polyethylene glycol, propylene glycol,liposomes, sugars such as mannitol and lactose, and a variety of othermaterials, again depending, on the specific type of formulation used. Asdescribed in Section IV, infra, dosage forms used for administration tothe vulvar region and/or vagina may be used to deliver drug on anas-needed, on-demand basis, and/or throughout an extended, sustainedrelease profile.

[0294] The formulations may also include a chemical compound to enhancepermeation of the active agent through the mucosal tissue, i.e., a“permeation enhancer.” Suitable permeation enhancers include thosegenerally useful in conjunction with topical, transdermal ortransmucosal drug delivery. Examples of suitable permeation enhancersinclude the following: sulfoxides such as dimethylsulfoxide (DMSO) anddecylmethylsulfoxide (C₁₀MSO); ethers such as diethylene glycolmonoethyl ether (available commercially as Transcutol®) and diethyleneglycol monomethyl ether; surfactants such as sodium laurate, sodiumlauryl sulfate, cetyltrimethylammonium bromide, benzalkonium chloride,Poloxamer (231, 182, 184), Tween (20, 40, 60, 80) and lecithin (U.S.Pat. No. 4,783,450); the 1-substituted azacycloheptan-2-ones,particularly 1-n-dodecylcyclaza-cycloheptan-2-one (available under thetrademark Azone® from Nelson Research & Development Co., Irvine, Calif.;see U.S. Pat. Nos. 3,989,816, 4,316,893, 4,405,616 and 4,557,934);alcohols such as ethanol, propanol, octanol, decanol, benzyl alcohol,and the like; fatty acids such as lauric acid, oleic acid and valericacid; fatty acid esters such as isopropyl myristate, isopropylpalmitate, methylpropionate, and ethyl oleate; polyols and estersthereof such as propylene glycol, ethylene glycol, glycerol, butanediol,polyethylene glycol, and polyethylene glycol monolaurate (PEGML; see,e.g., U.S. Pat. No. 4,568,343); amides and other nitrogenous compoundssuch as urea, dimethylacetamide (DMA), dimethylformamide (DMF),2-pyrrolidone, 1-methyl-2-pyrrolidone, ethanolamine, diethanolamine andtriethanolamine; terpenes; alkanones; and organic acids, particularlysalicylic acid and salicylates, citric acid and succinic acid. Mixturesof two or more enhancers may also be used.

[0295] In some cases, the formulations may include an enzyme inhibitor,i.e., a compound effective to inhibit enzymes present in the vagina orvulvar area that could degrade or metabolize the active agent. That is,inhibitors of enzymes that decrease or eliminate the activity of theactive agent may be included in the formulation so as to effectivelyinhibit the action of those enzymes. Such compounds include, forexample, fatty acids, fatty acid esters, and NAD inhibitors.

[0296] The formulations may be in the form of an ointment, cream,emulsion, lotion, gel, solid, solution, suspension, foam or liposomalformulation. Alternatively, the formulations may be contained within avaginal ring (e.g., as disclosed in U.S. Pat. No. 5,188,835 to Lindskoget al., assigned to Kabi Pharmacia AB), or within a tampon, suppository,sponge, pillow, puff, or osmotic pump system; these platforms are usefulsolely for vaginal delivery.

[0297] Ointments are semisolid preparations that are typically based onpetrolatum or other petroleum derivatives. The specific ointment base tobe used, as will be appreciated by those skilled in the art, is one thatwill provide for optimum drug delivery. As with other carriers orvehicles, an ointment base should be inert, stable, nonirritating andnonsensitizing. As explained in Remington: The Science and Practice ofPharmacy, supra, at pages 1034-1038, ointment bases may be grouped infour classes: oleaginous bases; emulsifiable bases; emulsion bases; andwater-soluble bases. Oleaginous ointment bases include, for example,vegetable oils, fats obtained from animals, and semisolid hydrocarbonsobtained from petroleum. Emulsifiable ointment bases, also known asabsorbent ointment bases, contain little or no water and include, forexample, hydroxystearin sulfate, anhydrous lanolin and hydrophilicpetrolatum. Emulsion ointment bases are either water-in-oil (W/O)emulsions or oil-in-water (O/W) emulsions, and include, for example,cetyl alcohol, glyceryl monostearate, lanolin and stearic acid.Preferred water-soluble ointment bases are prepared from polyethyleneglycols of varying molecular weight; again, reference may be had toRemington: The Science and Practice of Pharmacy for further information.

[0298] Lotions are preparations that may be applied without friction,and are typically liquid or semiliquid preparations in which solidparticles, including the active agent, are present in a water or alcoholbase. Lotions are usually suspensions of solids, and preferably, for thepresent purpose, comprise a liquid oily emulsion of the oil-in-watertype. It is generally necessary that the insoluble matter in a lotion befinely divided. Lotions will typically contain suspending agents toproduce better dispersions as well as compounds useful for localizingthe active agent in contact with the skin, e.g., methylcellulose, sodiumcarboxymethylcellulose, or the like.

[0299] Pharmaceutical emulsion formulations are generally formed from adispersed phase (e.g., a pharmacologically active agent), a dispersionmedium and an emulsifying agent. If desired, emulsion stabilizers can beincluded in the formulation as well. A number of pharmaceutically usefulemulsions are known in the art, including oil-in-water (o/w)formulations, water-in-oil (w/o) formulations and multiple emulsionssuch as w/o/w or o/w/o formulations. Emulsifying agents suitable for usein such formulations include, but are not limited to, TWEEN 60®, Span80®, cetostearyl alcohol, myristyl alcohol, glyceryl monostearate andsodium lauryl sulfate.

[0300] Pharmaceutical creams are, as known in the art, viscous liquid orsemisolid emulsions, either oil-in-water or water-in-oil. Cream basesare water-washable, and contain an oil phase, an emulsifier and anaqueous phase. The oil phase, also sometimes called the “internal”phase, is generally comprised of petrolatum and a fatty alcohol such ascetyl or stearyl alcohol; the aqueous phase usually, although notnecessarily, exceeds the oil phase in volume, and generally contains ahumectant. The emulsifier in a cream formulation is generally anonionic, anionic, cationic or amphoteric surfactant.

[0301] The above pharmaceutical formulations are formed by dispersingthe finely divided or dissolved active agent uniformly throughout thevehicle or base using conventional techniques, typically by a levigatingthe agent with a small quantity of the base to form a concentrate, whichis then diluted geometrically with further base. Alternatively, amechanical mixer may be used. Creams, lotions and emulsions are formedby way of a two-phase heat system, wherein oil-phase ingredients arecombined under heat to provide a liquified, uniform system. Theaqueous-phase ingredients are separately combined using heat. The oiland aqueous phases are then added together with constant agitation andallowed to cool. At this point, concentrated agents may be added as aslurry. Volatile or aromatic materials can be added after the emulsionhas sufficiently cooled. Preparation of such pharmaceutical formulationsis within the general skill of the art.

[0302] The active agent can also be incorporated into a gel formulationusing known techniques. Two-phase gel systems generally comprise asuspension or network of small, discrete particles interpenetrated by aliquid to provide a dispersed phase and a liquid phase. Single-phase gelsystems are formed by distributing organic macromolecules uniformlythroughout a liquid such that there are no apparent boundaries betweenthe dispersed and liquid phases. Suitable gelling agents for use hereininclude synthetic macromolecules (e.g., Carbomers®, polyvinyl alcoholsand polyoxyethylene-polyoxypropylene copolymers), gums such astragacanth, as well as sodium alginate, gelatin, methylcellulose, sodiumcarboxymethylcellulose, methylhydroxyethyl cellulose and hydroxyethylcellulose. In order to prepare a uniform gel, dispersing agents such asalcohol or glycerin can be added, or the gelling agent can be dispersedby trituration, mechanical mixing or stirring, or combinations thereof.

[0303] Liposomes are microscopic vesicles having a lipid wall comprisinga lipid bilayer, and can be used as drug delivery systems herein aswell. Generally, liposome formulations are preferred for poorly solubleor insoluble pharmaceutical agents. Liposomal preparations for use inthe instant invention include cationic (positively charged), anionic(negatively charged) and neutral preparations. Cationic liposomes arereadily available. For example,N[1-2,3-dioleyloxy)propyl]-N,N,N-triethylammonium (“DOTMA”) liposomesare available under the tradename Lipofectin® (GIBCO BRL, Grand Island,N.Y.). Similarly, anionic and neutral liposomes are readily available aswell, e.g., from Avanti Polar Lipids (Birmingham, Ala.), or can beeasily prepared using readily available materials. Such materialsinclude phosphatidyl choline, cholesterol, phosphatidyl ethanolamine,dioleoylphosphatidyl choline (“DOPC”), dioleoylphosphatidyl glycerol(“DOPG”), dioleoylphoshatidyl ethanolamine (“DOPE”), among others. Thesematerials can also be mixed with DOTMA in appropriate ratios. Methodsfor making liposomes using these materials are well known in the art.

[0304] Vaginal suppositories are typically manufactured withpolyethylene glycol (PEG), polyethylene oxide and/or other low meltingpoint or water-soluble polymers including fatty acid esters.Suppositories may also be applied to the vulvar region, in which casethese dosage forms, which are solid at ambient temperature, rapidlymelts when placed on the clitoris and within the vulvar region.

[0305] Typically, compositions and dosage forms for vulvar and/orvaginal administration will contain the active agent in a concentrationsuch that an effective amount of the agent is delivered with a singleapplication. For example, the composition or dosage form will generallycontain sufficient active agent such that an effective amount of theagent is delivered by application of about 0.1 g to 1.0 g. Thus, fordelivering about 1.0 μg to about 100 mg, preferably about 0.05 mg toabout 50 mg, most preferably about 1.0 mg to about 25 mg, of thecomposition or dosage form will contain the active agent at aconcentration in the range of about 1.0 μg/g to about 1.0 g/g,preferably 50 μg/g to about 500 mg/g, most preferably about 1.0 mg/g toabout 250 mg/g.

[0306] Delivery of an “as-needed” or “on-demand” dose with topicalformulations intended for application to the vulvar region, and/or withvaginal suppositories, is effected by using the appropriate carrier and,when necessary, excipients, for the particular active agent. Forexample, the active agent's affinity to the carrier must be lower thanits affinity to the treated body surface. Optimally, the agent will havea relatively high affinity for the mucosal surface to which it isapplied, and a relatively low affinity for the particular carrier. Asthe affinity of the agent for the body surface remains constant(assuming the agent does not change, e.g., hydrolyze, etc., upon contactwith the body surface), a suitable carrier for use in the formulationsdescribed herein can be determined by routinely testing a series ofdifferent carriers containing the active agent and selecting thosecarriers that provide the greatest flux of the active agent to theintended tissue, e.g., clitoral tissue. Additionally, one or morepermeation enhancers and/or detergents may also be present in theformulation to ensure a rate of delivery sufficient for on-demandadministration. A combination of these approaches as well as otherapproaches may be used to effect delivery of an on-demand dose.

[0307] Once the initial, on-demand dose is delivered, the drug deliverysystem, if present, and/or any remaining formulation may be removed ormay remain in place, depending on the preferences of the individual.Alternatively, the formulation and optional drug delivery system may bedesigned to provide both initial “on-demand” release of the activeagent, i.e., as a single, bolus dose, as well as sustained releasethereafter, e.g., pulsatile, continuous or cyclical drug release. Suchsystems can include, for example, osmotic release systems that arecapable of delivering an initial, on-demand release of the active agentin addition to variable amounts of the agent in a pulsatile mannerthereafter.

[0308] Other drug delivery platforms capable of providing an initialrelease of drug followed by a pulsatile, continuous or cyclical agentrelease profile include those formed from bioerodible polymers, whereinthe active agent is dispersed within a polymer matrix that is surroundedby an immediate release coating of the agent. The immediate releasecoating ensures effective on-demand administration. The polymers formingthe matrix are selected such that they bioerode in the presence ofmoisture, and provide for sustained agent release at readily predictablerates.

[0309] More particularly, release of the active agent can be controlledby dissolution (bioerosion) of a polymer using either encapsulateddissolution control or matrix dissolution control. In encapsulateddissolution control, the on-demand dose of the active agent is locatedwithin an outer polymeric or wax membrane that dissolves to provide aninitial release of the agent. When the encapsulating membrane comprisingan initial release of the agent has dissolved, a core containingadditional active agent is then available for release and adsorptionacross the epithelial or mucosal surfaces of the vagina or vulvar area.Bioerodible coating materials may be selected from a variety of naturaland synthetic polymers, depending on the agent to be coated and thedesired release characteristics. Exemplary coating materials includegelatins, carnauba wax, shellacs, ethylcellulose, cellulose acetatephthalate or cellulose acetate butyrate. Following the immediate releaseof the agent, a uniform sustained release of the agent can be attainedby compressing a population of particles of the agent with varyingmembrane thickness (e.g., varying erosion times) into a tablet form fora single administration.

[0310] In matrix dissolution control, the active agent is dissolved ordispersed within a matrix of, for example, an erodible wax. The agent isreleased for adsorption across the epithelial or mucosal surfaces of thevagina or vulvar area as the matrix bioerodes. The rate of agentavailability is generally controlled by the rate of penetration of thedissolution media (i.e., vaginal fluids) into the matrix, wherein therate of penetration is dependent on the porosity of the matrix material.Bioerodible matrix dissolution delivery systems can be prepared bycompressing the active agent with a slowly soluble polymer carrier intoa tablet or suppository form. There are several methods of preparingdrug/wax particles including congealing and aqueous dispersiontechniques. In congealing methods, the active agent is combined with awax material and either spray-congealed, or congealed and then screened.For an aqueous dispersion, the active agent/wax combination is sprayedor placed in water and the resulting particles collected. Matrix dosageformulations can be formed by compaction or compression of a mixture ofactive agent, polymer and excipients. Of course, the active agent willalso be located in an external coating of the matrix formulation toprovide for immediate release of the active agent necessary foron-demand administration.

[0311] In an alternative embodiment, the pharmaceutical formulation isadministered in the form of biodegradable adhesive film or sheet thatadheres to the vulvar area. Such drug delivery systems are generallycomposed of a biodegradable adhesive polymer based on a polyurethane, apoly(lactic acid), a poly(glycolic acid), a poly(ortho ester), apolyanhydride, a polyphosphazene, or a mixture or copolymer thereof.Preferred biodegradable adhesive polymers include polyurethanes andblock copolyurethanes containing peptide linkages, simple mixtures ofpolyurethanes and polylactides, and copolymers of acrylates and mono- ordisaccharide residues.

[0312] Preferred dosage forms contain a unit dose of active agent, i.e.,a single therapeutically effective dose. For creams, ointments, etc., a“unit dose” requires an active agent concentration that provides a unitdose in a specified quantity of the formulation to be applied, asexplained supra. The unit dose of any particular active agent willdepend, of course, on the active agent, the needs of the patient, and onthe mode of administration. Those of ordinary skill in the art ofpharmaceutical formulation can readily deduce suitable unit doses forVIP and various VIP agonists, as well as suitable unit doses for othertypes of active agents that may be incorporated into a dosage form ofthe invention.

[0313] Drug administration is preferably, although not necessarily, onan as-needed basis, in which case chronic drug administration is notinvolved. With an immediate release dosage form, i.e., a composition ordosage form that is not “controlled release” as defined hereinabove,as-needed administration may involve drug administration immediatelyprior to sexual activity, but will generally be in the range of about0.25 to 72 hours, preferably about 0.5 to 48 hours, more preferablyabout 1 to 24 hours, most preferably about 1 to 12 hours, and optimallyabout 1 to 4 hours prior to anticipated sexual activity. As will beappreciated by those in the fields of pharmacology and drug delivery,the upper end of the aforementioned ranges will depend on thepharmacokinetics of the particular active agent administered.

[0314] With a sustained release dosage form, a single “as-needed” dosecan provide therapeutic efficacy over an extended time period in therange of about 4 to 72 hours, typically in the range of about 4 to 48hours, more typically in the range of about 4 to 24 hours, depending onthe formulation. The release period may be varied by the selection andrelative quantity of particular sustained release polymers, as discussedsupra.

[0315] As-needed administration as described herein has severaladvantages over chronic pharmacologic intervention. First, chronicadministration of some agents, in particular steroids, can result inserious medical complications and alter the balance of naturallyoccurring steroids in the body. Second, patient compliance can beproblematic with a regimented dosing scheme. Furthermore, as-neededadministration is convenient and doses are taken only in anticipation ofsexual activity. Thus, needless expenditure on wasted dosages isavoided, thereby decreasing the treatment's overall expense.

[0316] The patient treated may be a woman suffering from some type ofsexual dysfunction or disorder, or may possess “normal” sexual desireand/or “normal” sexual responsiveness as those terms are understooddefined by clinicians or other experts. For these “normal” women, thepresent invention offers heightened sexual desire and responsivenessrelative to her typical sexual experience. Often, however, the femalepatient seeking enhanced sexual desire and responsiveness suffers asexual dysfunction such as a condition, disease or disorder that affectsone of the four stages of the female sexual response: excitement,plateau, orgasm, or resolution. More specifically, the patient maysuffer from any one or more of the following:

[0317] a decrease in or absence of female sexual responsiveness orfemale sexual desire;

[0318] a persistent or recurrent deficiency or absence of sexualfantasies and desire for sexual activity;

[0319] a decrease in the physiological response to sexual stimulationsuch as, but not limited to, slowed, decreased or absent erectileresponse of the female erectile tissues; slowed, decrease or absentlubrication of the vagina; slowed decreased or absent ability to reachorgasm, and decreased intensity of or pleasure in orgasms;

[0320] frigidity;

[0321] sexual aversion;

[0322] a condition, disease or disorder that may result in decreasedsexual desire and responsiveness including, but not limited to, themenopausal or post-menopausal state, radiotherapy of the pelvis,multiple sclerosis, atherosclerosis, pelvic trauma or surgery,peripheral neuropathies, autonomic neuropathies, diabetes mellitus, anddisorders of the innervation of any of the sexual organs;

[0323] substance-induced decreases in sexual desire and responsivenessincluding, but not limited to, decreases related to the administrationof pharmacologic agents such as, but not limited to, anti-depressants,neuroleptics, anti-hypertensives, opiates, alcohol, and any other agentfound to decrease or eliminate any part of the sexual response cycle;and

[0324] primary and secondary anorgasmia.

[0325] In addition to enhancing female sexual desire and responsiveness,the method, compositions and dosage forms of the invention are useful inimproving the tissue health of the female genitalia and preventingvaginal atrophy, preventing pain during intercourse as a result ofdyspareunia, and alleviating vaginal itching and dryness associated withdyspareunia and other conditions.

[0326] In another embodiment, a packaged kit is provided that containsthe pharmaceutical formulation to be administered, i.e., apharmaceutical formulation containing VIP or a VIP agonist for enhancingfemale sexual desire and responsiveness, a container (e.g., a vial, abottle, a pouch, an envelope, a can, a tube, an atomizer, an aerosolcan, etc.), preferably sealed, for housing the formulation duringstorage and prior to use, and instructions for carrying out drugadministration in a manner effective to enhance sexual desire andresponsiveness. The instructions will typically be written instructionson a package insert, a label, and/or on other components of the kit.

[0327] Depending on the type of formulation and the intended mode ofadministration, the kit may also include a device for administering theformulation (e.g., a transdermal delivery device). The administrationdevice may be a dropper, a swab, a stick, or the nozzle or outlet of anatomizer or aerosol can. The formulation may be any suitable formulationas described herein. For example, the formulation may be an oral dosageform containing a unit dosage of the active agent, or a gel or ointmentcontained within a tube. The kit may contain multiple formulations ofdifferent dosages of the same agent. The kit may also contain multipleformulations of different active agents.

[0328] The present kits will also typically include means for packagingthe individual kit components, i.e., the pharmaceutical dosage forms,the administration device (if included), and the written instructionsfor use. Such packaging means may take the form of a cardboard or paperbox, a plastic or foil pouch, etc.

[0329] It is to be understood that while the invention has beendescribed in conjunction with the preferred specific embodimentsthereof, that the foregoing description as well as the examples thatfollow are intended to illustrate and not limit the scope of theinvention. Other aspects, advantages and modifications within the scopeof the invention will be apparent to those skilled in the art to whichthe invention pertains.

[0330] All patents, patent applications, patent publications andnon-patent literature references mentioned herein are incorporated byreference in their entireties.

EXAMPLE 1

[0331] A cream formulation is prepared for the topical administration ofVIP. The cream includes the following components: VIP 750 mg Beeswax 2.7g Carbopol ® 934 q.s. 100.0 g

[0332] Mixing is conducted with tile and spatula until a homogeneouscream mixture is obtained having the prostaglandin uniformly dispersedthroughout the composition.

EXAMPLE 2

[0333] The procedure of Example 1 is repeated except that the followingcomponents are used: Stearyl-VIP 500 mg Polyethylene glycol 400 37.5 g1,2,6-hexanetriol 20.0 g Polyethylene glycol 4000 q.s. 100.0 g

[0334] Stearyl-VIP is prepared as described in U.S. Pat. No. 5,147,855to Gozes et al. A homogenous cream mixture is obtained.

EXAMPLE 3

[0335] The procedure of Example 1 is repeated except that the followingcomponents are used: Stearyl VIP₇₋₂₈ 750 mg Polyethylene glycol 400 37.0g Polyethylene glycol 400 monostearate 26.0 g Polyethylene glycol 4000q.s. 100.0 g

[0336] Stearyl-VIP is prepared as described in U.S. Pat. No. 5,147,855to Gozes et al. A homogenous cream mixture is obtained.

EXAMPLE 4

[0337] The procedure of Example 1 is repeated except that the followingcomponents are used: VIP-Gly-Cys-NH₂ (SEQ. ID NO.: 204) 750 mgPolyethylene glycol 400 47.5 g Cetyl Alcohol 5.0 g Polyethylene glycol4000 q.s. 100.0 g

[0338] VIP-Gly-Cys-NH₂ (SEQ. ID NO.: 204) is prepared as described inU.S. Pat. No. 5,612,314 to Stamler et al. A homogenous cream mixture isobtained.

EXAMPLE 5

[0339] The procedure of Example 1 is repeated except that the followingcomponents are used: VIP-Gly-Cys-NO (SEQ. ID NO.: 203) 750 mgPolyethylene glycol 400 47.5 g Cetyl Alcohol 5.0 g Polyethylene glycol4000 q.s. 100.0 g

[0340] VIP-Gly-Cys-NO (SEQ. ID NO.: 203) is prepared as described inU.S. Pat. No. 5,612,314 to Stamler et al. A homogenous cream mixture isobtained.

EXAMPLE 6

[0341] An ointment formulation is prepared for the topicaladministration of VIP. The ointment includes the following components:VIP 750 mg Anhydrous lanolin 20.0 g Mineral oil 25.0 g White Petrolatumq.s. 100.0 g

[0342] Mixing is conducted with tile and spatula until a homogeneousointment mixture is obtained having the VIP uniformly dispersedthroughout the composition.

EXAMPLE 7

[0343] The procedure of Example 5 is repeated except that the followingcomponents are used: VIP 750 m Diisopropyl Adipate 19.95 g WhitePetrolatum, USP q.s. 100.0 g

[0344] A homogenous ointment mixture is obtained.

[0345] In the cream and ointment formulations described in Examples 1-6,optional ingredients can include materials such as antioxidants,viscosity modifiers (e.g., paraffin wax or lanolin wax), and topicalabsorption rate modifiers.

EXAMPLE 8

[0346] A vaginal suppository formulation is prepared using a syntheticor semisynthetic prostaglandin. The suppository includes the followingcomponents: Prostaglandin 0.25 gm Polyethylene glycol 400 37.0 gmGlycerol gelatin 20.0 gm Polyethylene glycol 4000 q.s. 100.0 gm

[0347] The polyethylene glycol 400 solution containing prostaglandin ismixed well with glycerol gelatin or similar suppository base such asmacrogol, Witepsol®, or the like, with a mechanical mixing apparatus,and the mixture is then cooled in a suppository mold.

EXAMPLE 9

[0348] Suppositories suitable for vaginal administration of a unitdosage of VIP are made as follows. Twenty mg VIP are mixing the selectedprostaglandin with 250 mg polyethylene glycol, molecular weight (M_(w))approximately 4000, and the mixture is heated to a temperature just highenough to produce a melt. The melted mixture is then poured into a moldsuitable to provide a suppository, and allowed to cool. The suppositoryso provided is a unit dosage form suitable for vaginal administration.

EXAMPLE 10

[0349] Individuals are assessed and pre-screened to assemble anexperimental group of subjects suffering from sexual dysfunction. Thecompositions prepared in Examples 1-9, formulated with VIP or an analogthereof, are each assessed in the experimental subjects for theirability to increase uterine or vaginal epithelial blood flow. Theformulations are applied vaginally and to the vulvar region, and changesin blood flow and/or vaginal fluid production after application of thevasodilating formulations are determined using known methods. Increasein vaginal epithelial blood flow is determined using indirect methodssuch as photoplethysmography (Levin (1980) Clinics in Obstet. Gynaecol.7:213-252), heated oxygen electrode (Wagner et al. (1978), “VaginalFluid” in The Human Vagina, Evans et al. (eds.), Amsterdam:Elsevier/North Holland Biomedical Press, pp. 121-137), and directclearance of radioactive Xenon (Wagner et al. (1980) Obstet. Gynaecol.56:621-624). Changes in vulvar blood flow are monitored using laserDoppler velocimetry (Sarrel, P. M. (1990) Obstet. Gynaecol. 75:26S-32S).

[0350] Decreased vaginal dryness and/or dyspareunia are negativelycorrelated with vaginal blood flow rates, wherein increased blood flowto the vagina correlates with increased lubrication and decreasedfrequency and severity of dyspareunia (Sarrel, P. M. (1990) Obstet.Gynaecol. 75:26S-32S). Accordingly, vulvar blood flow after treatment isassessed using laser Doppler velocimetry and compared to baselinelevels. Increased vaginal lubrication as a result of treatment with thevasoactive formulations can also be assessed using the methods ofSemmens et al. (1982) J. Am. Med. Assoc. 248:445-448. The compositionsof Examples 1-9, when assessed using such methods, are found tosubstantially increase blood flow to the vagina and vulvar area andalleviate vaginal dryness.

1. A method for treating sexual dysfunction in a female individual,comprising administering to the vagina and/or vulvar region of theindividual a pharmaceutical formulation that comprises a therapeuticallyeffective amount of a vasoactive agent selected from the groupconsisting vasoactive intestinal polypeptide and agonists thereof. 2.The method of claim 1, wherein the pharmaceutical formulation furtherincludes a pharmaceutically acceptable carrier suited to vaginal and/orvulvar drug administration.
 3. The method of claim 1, flurther includingadministering a steroid to the vagina and/or vulvar region of theindividual.
 4. The method of claim 3, wherein the steroid is selectedfrom the group consisting of progestins, estrogens, androgens, andcombinations thereof.
 5. The method of claim 1, wherein thepharmaceutical formulation further includes a compound selected from thegroup consisting of steroid agonists, partial agonists and antagonists.6. The method of claim 1, wherein the pharmaceutical formulation iscontained within a delivery system selected to provide a predeterminedagent release profile.
 7. The method of claim 6, wherein the agentrelease profile is pulsatile.
 8. The method of claim 6, wherein theagent release profile is continuous.
 9. The method of claim 6, whereinthe agent release profile is cyclical.
 10. The method of claim 6,wherein the agent release profile is diurnal.
 11. The method of claim 1,wherein the pharmaceutical formulation is administered vaginally. 12.The method of claim 11, wherein the pharmaceutical formulation is in theform of an ointment, cream, gel, solid, solution, suspension, foam orliposomal composition.
 13. The method of claim 11, wherein thepharmaceutical formulation is contained within a vaginal ring, tampon,suppository, sponge, pillow, puff, or osmotic pump system.
 14. Themethod of claim 1, wherein the pharmaceutical formulation isadministered to the vulvar region.
 15. The method of claim 1, whereinthe vasoactive agent is vasoactive intestinal polypeptide.
 16. Themethod of claim 1, wherein the vasoactive agent is a vasoactiveintestinal polypeptide agonist.
 17. The method of claim 16, wherein thevasoactive intestinal polypeptide agonist comprises a polypeptidesequence comprising a human vasoactive intestinal polypeptide sequencehaving amino acid substitutions at one or more positions.
 18. The methodof claim 17, wherein the vasoactive intestinal polypeptide agonist isterminally modified.
 19. The method of claim 16, wherein the vasoactiveintestinal peptide agonist comprises at least one agonist selected fromthe group consisting of SEQ. ID. NOS.:2-205 inclusive.
 20. The method ofclaim 4, wherein the steroid is an androgenic agent.
 21. The method ofclaim 20, wherein the androgenic agent is selected from the groupconsisting of androsterone, androsterone acetate, androsteronepropionate, androsterone benzoate, androstenediol,androstenediol-3-acetate, androstenediol-17-acetate,androstenediol-3,17-diacetate, androstenediol-17-benzoate,androstenediol-3-acetate-17-benzoate, androstenedione,dehydroepiandrosterone, sodium dehydroepiandrosterone sulfate,4-dihydrotestosterone, dromostanolone, dromostanolone propionate,ethylestrenol, fluoxymesterone, methyltestosterone, nandrolonephenpropionate, nandrolone decanoate, nandrolone furylpropionate,nandrolone cyclohexane-propionate, nandrolone benzoate, nandrolonecyclohexanecarboxylate, oxandrolone, oxymetholone, stanozolol,testolactone, testosterone, and pharmaceutically acceptable esters oftestosterone and 4-dihydrotestosterone.
 22. The method of claim 21,wherein the androgenic agent is selected from the group consisting oftestosterone, C-17 esters of testosterone, 4-dihydrotestosterone, C-17esters of 4-dihydrotestosterone, dehydroepiandrosterone, andmethyltestosterone.
 23. A method for enhancing sexual desire andresponsiveness in a female individual, comprising administering to theindividual, approximately 0.25 to 72 hours prior to sexual activity, atherapeutically effective amount of a vasoactive agent selected from thegroup consisting of vasoactive intestinal polypeptide, agonists thereof,and combinations thereof.
 24. A method for maintaining improving thetissue health of the female genitalia, comprising administering to afemale individual, on an as-needed basis, a therapeutically effectiveamount of a vasoactive agent selected from the group consisting ofvasoactive intestinal polypeptide, agonists thereof, and combinationsthereof.
 25. A method for preventing vaginal atrophy, comprisingadministering to a female individual, on an as-needed basis, atherapeutically effective amount of a vasoactive agent selected from thegroup consisting of vasoactive intestinal polypeptide, agonists thereof,and combinations thereof.
 26. A method for preventing vaginal painduring sexual intercourse, comprising administering to a femaleindividual suffering from dyspareunia a therapeutically effective amountof a vasoactive agent selected from the group consisting of vasoactiveintestinal polypeptide, agonists thereof, and combinations thereof. 27.A method for alleviating vaginal itching and dryness, comprisingadministering to a female individual in need of such treatment atherapeutically effective amount of a vasoactive agent selected from thegroup consisting of vasoactive intestinal polypeptide, agonists thereof,and combinations thereof, on an as-needed basis.
 28. A method forenhancing sexual desire and responsiveness in a female individual,comprising administering a vasoactive agent selected from the groupconsisting of vasoactive intestinal polypeptide, agonists thereof, andcombinations thereof to the individual in an amount effective to providea blood level of the agent or a metabolite thereof that approximates theblood level of the agent or a metabolite thereof during ovulation.
 29. Apharmaceutical formulation for enhancing female sexual desire andresponsiveness, comprising (a) approximately 1.0 μg to 1.0 g of avasoactive agent selected from the group consisting of vasoactiveintestinal polypeptide, agonists thereof, and combinations thereof, pergram of formulation, (b) a pharmaceutically acceptable carrier suitablefor vaginal and/or vulvar administration.
 30. The formulation of claim29, wherein the formulation comprises approximately 50 μg to about 500mg of the vasoactive agent per gram of formulation.
 31. The formulationof claim 30, wherein the formulation comprises approximately 1.0 mg toabout 250 mg of the vasoactive agent per gram of formulation.
 32. Theformulation of claim 29, wherein the carrier is selected to provideimmediate release of the vasoactive agent from the formulation followingapplication to the individual's vagina and/or vulvar area, such that theformulation may be effectively administered on an on-demand basis. 33.The formulation of claim 29, comprising a gel, cream, ointment, solutionor lotion.
 34. The formulation of claim 29, comprising a suppository.35. The formulation of claim 29, wherein the vasoactive agent isvasoactive intestinal polypeptide.
 36. The formulation of claim 29,wherein the vasoactive agent is a vasoactive intestinal polypeptideagonist.
 37. The formulation of claim 36, wherein the vasoactiveintestinal polypeptide agonist comprises a polypeptide sequencecomprising a human vasoactive intestinal polypeptide sequence havingamino acid substitutions at one or more positions.
 38. The formulationof claim 37, wherein the vasoactive intestinal polypeptide agonist isterminally modified.
 39. The formulation of claim 36, wherein thevasoactive intestinal peptide agonist comprises at least one agonistselected from the group consisting of SEQ. ID. NOS.:2-205 inclusive. 40.A packaged kit for a female individual to use in enhancing sexual desireand responsiveness, comprising: a pharmaceutical formulation of avasoactive agent selected from the group consisting of vasoactiveintestinal polypeptide and agonists thereof; a container housing thepharmaceutical formulation during storage and prior to administration;and instructions for carrying out drug administration to enhance sexualdesire and responsiveness.